No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Chronic Phantom Limb Pain: The Effects of Calcitonin, Ketamine, and Their Combination on Pain and Sensory Thresholds
Abstract
Calcitonin was effective in a study of acute phantom limb pain, but it was not studied in the chronic phase. The overall literature on N-methyl-D-aspartate antagonists is equivocal. We tested the hypothesis that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Our secondary aim was to improve our understanding of the mechanisms of action of the investigated drugs using quantitative sensory testing.
Twenty patients received, in a randomized, double-blind, crossover manner, 4 i.v. infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion.
Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral side except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds.
Our results question the usefulness of calcitonin in chronic phantom limb pain and stress the potential interest of N-methyl-D-aspartate antagonists. Sensory assessments indicated that peripheral mechanisms are unlikely important determinants of phantom limb pain. Ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain.
... Our search strategy yielded 4108 articles, of which 2296 were excluded as duplicates during prescreening and 1783 were excluded by title/abstract screening. Twenty-nine articles were eligible for full-text screening and of these, six articles were identified as meeting the criteria for inclusion in the narrative synthesis [42][43][44][45][46][47]. A PRISMA flowchart of Fig. 1 Flowchart of the systematic review the screening and selection process is presented in Fig. 1. ...
... A PRISMA flowchart of Fig. 1 Flowchart of the systematic review the screening and selection process is presented in Fig. 1. Eligible articles were grouped by study design into openlabel studies (n = 2) [42,43], prospective observational studies (n = 1) [45], and randomized clinical trials (n = 3) [44,46,47]. ...
... Three of the six papers were rated as moderate methodological quality [44,46,47], and the remaining three were rated as low methodological quality [42,43,45] on the Downs and Black checklist ( Table 1). The data extracted from the included studies for analysis are summarized in Table 2. Eichenberger et al. [46] Simanski et al. [45] Jaeger and Maier [44] Kessel and Wörz [43] Mertz [42] Reporting 1. Hypothesis/objective clearly described ...
Introduction:
Phantom limb pain (PLP) refers to pain perceived in a part of the body removed by amputation or trauma. Despite the high prevalence of PLP following amputation and the significant morbidity associated with it, robust therapeutic approaches are currently lacking. Calcitonin, a polypeptide hormone, has recently emerged as a novel analgesic with documented benefits in the treatment of several pain-related conditions.
Methods:
We present a systematic review that comprehensively evaluates the analgesic effects of calcitonin for patients with PLP. We searched MEDLINE, OLDMEDLINE, and PubMed Central databases with the key words "calcitonin" "phantom limb pain" and "phantom pain" to identify clinical studies evaluating the efficacy or effectiveness of calcitonin administration, in any form and dose, for the treatment of PLP. Additionally, Google Scholar was searched manually with the search term "calcitonin phantom limb pain". All four databases were searched from inception until 1 December 2022. The methodological quality of each included study was assessed using the Downs and Black checklist and the GRADE criteria were used to assess effect certainty and risk of bias.
Results:
Our search identified 4108 citations, of which six ultimately met the criteria for inclusion in the synthesis. The included articles described a mix of open-label (n = 2), prospective observational cohort (n = 1), and randomized clinical trials (n = 3). The most common treatment regimen in the current literature is a single intravenous infusion of 200 IU salmon-derived calcitonin.
Conclusion:
The available evidence supported the use of calcitonin as either monotherapy or adjuvant therapy in the treatment of PLP during the acute phase, while the evidence surrounding calcitonin treatment in chronic PLP is heterogeneous. Given the limited treatment options for the management of PLP and calcitonin's relatively wide therapeutic index, further research is warranted to determine the role that calcitonin may play in the treatment of PLP and other pain disorders.
... Table 1 provides an overview of the characteristics of the 19 newly included studies (N 5 2776) and the 21 studies (N 5 1965) reviewed in 2012. 9 Among these trials involving 36 different systemic and topical drug combinations, 6 studies evaluated the combination of an opioid with a gabapentinoid (931 participants, with tapentadol being classified as an opioid) 5,8,15,25,36,72 ; 4 studies evaluated the combination of an opioid with an antidepressant (138 participants) 30,37,44,54 ; 3 studies evaluated the combination of a gabapentinoid with an antidepressant (472 participants) 24,41,68 ; 5 studies evaluated the combination of ketamine with an agent from a different drug class (152 participants) 3,17,58,61,69 ; 7 studies involved a combination with topical analgesics (1094 participants) 2,6,22,23,47,48,51 ; and 15 studies evaluated various other analgesic combinations (1954 participants). 4,10,13,20,31,32,34,45,46,50,52,60,63,64,71 Neuropathic pain conditions studied were peripheral neuropathic pain (diabetic neuropathy and postherpetic neuralgia), 30 low back pain with a neuropathic component, 5 HIV-associated polyneuropathy, 37 lumbar radiculopathy, 44 neuropathic cancer pain, 8,10,15,50,54 , chemotherapy-induced peripheral neuropathic pain, 6,23 diabetic neuropathy, 2,20,24,25,31,32,60,63,64,68,69,72 postherpetic neuralgia, 22,24,25,34,69,72 chronic/refractory neuropathic pain of mixed etiology, 47,48,52,58,61 multiple sclerosis, 71 lumbar spinal stenosis, 45 radiation-induced plexopathy, 13 Charcot-Marie-Tooth disease type 1A, 4 chronic phantom limb pain, 17 and spinal cord injury-related chronic neuropathic pain. ...
... 9 Among these trials involving 36 different systemic and topical drug combinations, 6 studies evaluated the combination of an opioid with a gabapentinoid (931 participants, with tapentadol being classified as an opioid) 5,8,15,25,36,72 ; 4 studies evaluated the combination of an opioid with an antidepressant (138 participants) 30,37,44,54 ; 3 studies evaluated the combination of a gabapentinoid with an antidepressant (472 participants) 24,41,68 ; 5 studies evaluated the combination of ketamine with an agent from a different drug class (152 participants) 3,17,58,61,69 ; 7 studies involved a combination with topical analgesics (1094 participants) 2,6,22,23,47,48,51 ; and 15 studies evaluated various other analgesic combinations (1954 participants). 4,10,13,20,31,32,34,45,46,50,52,60,63,64,71 Neuropathic pain conditions studied were peripheral neuropathic pain (diabetic neuropathy and postherpetic neuralgia), 30 low back pain with a neuropathic component, 5 HIV-associated polyneuropathy, 37 lumbar radiculopathy, 44 neuropathic cancer pain, 8,10,15,50,54 , chemotherapy-induced peripheral neuropathic pain, 6,23 diabetic neuropathy, 2,20,24,25,31,32,60,63,64,68,69,72 postherpetic neuralgia, 22,24,25,34,69,72 chronic/refractory neuropathic pain of mixed etiology, 47,48,52,58,61 multiple sclerosis, 71 lumbar spinal stenosis, 45 radiation-induced plexopathy, 13 Charcot-Marie-Tooth disease type 1A, 4 chronic phantom limb pain, 17 and spinal cord injury-related chronic neuropathic pain. 3 Copyright © 2022 by the International Association for the Study of Pain. ...
... Of 40 studies, 24 were parallel design (3903 participants), 2-6,8,10,13,20,23,34,36,45,46,48,50,51,61,63,64,68,69,71,72 and 16 were crossover design (838 participants). 15,17,22,24,25,[30][31][32]37,41,44,47,52,54,58,60 Ten studies were of less than 3-week treatment duration (502 participants). 3,8,10,15,17,22,47,50,52,54 In total, 19 of 40 (48%) included studies had at least 4 of 7 items that qualified as low risk of bias (Supplementary Figs. 1 and 2, available at http://links.lww.com/ ...
Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. Over half of patients receive 2 or more analgesics and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind RCTs evaluating combinations of two or more drugs versus placebo and/or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects, and risk-of-bias was assessed. Meta-analyses compared combination to monotherapy wherever two or more similar studies were available. Forty studies (4,741 participants) were included. Studies were heterogenous with respect to various characteristics including dose titration methods and administration (i.e. simultaneous versus sequential) of the combination. Few combinations involved a non-sedating drug and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared to monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy - as second- or third-line treatment - in situations where monotherapy is insufficient should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving non-sedating agents, and to identify clinical settings and specific combinations that safely provided added benefit.
... Alternative treatment options, such as the use of infusion therapies with lidocaine [21][22][23][24] or ketamine [25,26], have received attention in the treatment of several chronic pain conditions. Studies using lidocaine and ketamine as a treatment approach have shown a benefit with regard to both immediate pain reduction and longer lasting pain relief. ...
... Sleigh et al. have suggested that ketamine may suppress pain signal transmission by inhibiting astrocyte and microglial activation [41]. Ketamine has shown beneficial effects in studies investigating its use in chronic regional pain syndrome [26], fibromyalgia [42], chronic phantom limb pain [25], postherpetic neuralgia [43] and neuropathic pain [44]. ...
Background: Infusions with lidocaine or ketamine have been separately established in the treatment of chronic pain. This study aims to retrospectively evaluate the effect of combined infusions of lidocaine and ketamine. Materials & methods: Patient records were screened for receipt of combined ambulatory infusions of lidocaine and ketamine from 2012 through 2021. A scoring system was designed to assess pain response retrospectively. Results: A total of 319 patients were included. Median pain reduction in days was 10.00 (interquartile range: 13.25). Side effects were limited to the acute phase of infusions. A total of 41.4% of patients who received concomitant pain medication reported a dose reduction. Conclusion: Our data support combined infusions as a safe therapy option, with good short-, medium- and long-term reductions in pain and great heterogeneity in treatment response.
Clinical trial registration: ClinicalTrials.gov (NCT05103319)
... [5][6][7][8][9][10][11][12][13] Ketamine significantly reduces neuropathic pain compared with placebo by 25% [13][14][15] to 45% and by 35% in other studies. [16,17] Many double-blinded randomized controlled trials (RCTs) confirmed its analgesic effect, [16,[18][19][20][21][22][23] but the duration of effect was reported as low as 2 h in some studies, [24,25] and up to several weeks [26] or several months in other studies. [27] However, the used protocols are different, the results show a significant inter-individual variation (regarding the effectiveness, the onset of action, and durability), and the diseases treated by ketamine are multiple. ...
... [5][6][7][8][9][10][11][12][13] Ketamine significantly reduces neuropathic pain compared with placebo by 25% [13][14][15] to 45% and by 35% in other studies. [16,17] Many double-blinded randomized controlled trials (RCTs) confirmed its analgesic effect, [16,[18][19][20][21][22][23] but the duration of effect was reported as low as 2 h in some studies, [24,25] and up to several weeks [26] or several months in other studies. [27] However, the used protocols are different, the results show a significant inter-individual variation (regarding the effectiveness, the onset of action, and durability), and the diseases treated by ketamine are multiple. ...
Background:
Intravenous (IV) ketamine is used for chronic neuropathic pain refractory to other treatments. Administration of such a medication requires high-cost services while the result is not always satisfactory with a significant percentage of failure. Success and failure are related to some factors.
Method:
In this study, we aim to point the most responsive disease category to IV ketamine and the predictive factors for successful and failed treatment. Two hundred and sixty-nine patients out of 371 were included. Demographic, clinical, and therapy-related variables were retrospectively collected and then statistically analyzed using various descriptive and inferential methods. A few descriptive statistics are obtained for the variables depending on their nature (e.g., percentages for qualitative variables and means for quantitative variables). Furthermore, several inferential methods are considered to address some statistical points of interest, including, but not limited to, odds ratio interpretations via logistic regression as well as association and correlation analyses.
Results:
A significant association was found between the presence of intermittent pain pattern as well as the pain of chronic primary category and favorable response to IV ketamine while the history of previous analgesic interventions was significantly associated with a negative response.
Conclusion:
The identified factors can be used to prospectively study the efficacy of ketamine using selection criteria based on the observed results in our study to re-evaluate the percentage of responsiveness according to these new parameters.
... Alviar et al. reviewed three NMDA receptor antagonists as possibilities: memantine, dextromethorphan, and ketamine (Alviar et al., 2016). The review identified only ketamine (Eichenberger et al., 2008) and dextromethorphan (Ben Abraham et al., 2003) to provide pain relief from this class of pharmacologic interventions (Alviar et al., 2016); however, both studies were underpowered (Alviar et al., 2016) and treatment with ketamine had substantial side effects, including dizziness, light hallucinations, and hearing impairment (Eichenberger et al., 2008). NMDA receptor antagonists have shown moderate success at relieving pain. ...
... Alviar et al. reviewed three NMDA receptor antagonists as possibilities: memantine, dextromethorphan, and ketamine (Alviar et al., 2016). The review identified only ketamine (Eichenberger et al., 2008) and dextromethorphan (Ben Abraham et al., 2003) to provide pain relief from this class of pharmacologic interventions (Alviar et al., 2016); however, both studies were underpowered (Alviar et al., 2016) and treatment with ketamine had substantial side effects, including dizziness, light hallucinations, and hearing impairment (Eichenberger et al., 2008). NMDA receptor antagonists have shown moderate success at relieving pain. ...
... A study by Jaeger et al found calcitonin effective in treating phantom pain, but another study by Eichenberger did not find any efficacy in treating PLP. 62,63 Dextromethorphan has also shown some efficacy in the treatment of phantom pain in a small study, most likely through inhibition of NMDA receptor hyperexcitability. 61 Intravenous ketamine infusions have shown some potential in treating PLP. ...
... They concluded that ketamine may be helpful, while calcitonin did not demonstrate efficacy when compared to placebo in the treatment of PLP. 63 A 2018 review of single and combined pharmacologic management of PLP by Hall and Eldabe found that only NMDA antagonists, namely ketamine, produced consistent positive results. Most notably, ketamine infusions reduced pain pressure thresholds and windup, presumably by limiting central sensitization. ...
Jacob Boomgaardt,1 Kovosh Dastan,1 Tiffany Chan,2 Ashley Shilling,2 Alaa Abd-Elsayed,3 Lynn Kohan2 1Department of Physical Medicine and Rehabilitation, University of Virginia, Charlottesville, VA, USA; 2Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA; 3Department of Anesthesiology, University of Wisconsin-Madison, Madison, WI, USACorrespondence: Lynn Kohan, Department of Anesthesiology, University of Virginia, 545 Ray C Hunt Suite 3168, Charlottesville, VA, 22903, USA, Tel +1-434-243-5676, Fax +1-434-243-5689, Email Lrk9g@hscmail.mcc.virginia.eduAbstract: Phantom limb pain (PLP) is a common condition that occurs following both upper and lower limb amputation. First recognized and described in 1551 by Ambroise Pare, research into its underlying pathology and effective treatments remains a very active and growing field. To date, however, there is little consensus regarding the optimal management of phantom limb pain. With few large well-designed clinical trials of which to make treatment recommendations, as well as significant heterogeneity in clinical response to available treatments, the management of PLP remains challenging. Below we summarize the current state of knowledge in the field, as well as propose an algorithm for the approach to the treatment of PLP.Keywords: phantom pain, phantom sensations, stump pain, residual limb pain
... In another randomized, controlled study involving 160 pregnant women undergoing cesarean section with spinal anesthesia, 5 minutes after delivery, patients who received 0.25 mg/kg intravenous ketamine via bolus doses significantly reduced the requirement for analgesics and had fewer side effects caused by opioids, compared with those in the control group who received normal saline solution after delivery (13). Ketamine has also been successfully used in phantom pain (14)(15)(16), although a recent case report demonstrated a lack of efficacy when ketamine is used for this purpose (17). In a randomized, double-blind, and crossover study of 20 patients, ketamine (0.4 mg/kg IV), but not calcitonin, was shown to reduce phantom limb pain (14), which was supported by a double-blind, saline-controlled study in which 11 patients had decreased stump and phantom limb pain scores as a response to ketamine (0.1 mg/kg/5 min IV bolus, followed by an infusion rate of 7 µg/kg/min) (16). ...
... Ketamine has also been successfully used in phantom pain (14)(15)(16), although a recent case report demonstrated a lack of efficacy when ketamine is used for this purpose (17). In a randomized, double-blind, and crossover study of 20 patients, ketamine (0.4 mg/kg IV), but not calcitonin, was shown to reduce phantom limb pain (14), which was supported by a double-blind, saline-controlled study in which 11 patients had decreased stump and phantom limb pain scores as a response to ketamine (0.1 mg/kg/5 min IV bolus, followed by an infusion rate of 7 µg/kg/min) (16). Recently, ketamine has been found to have antidepressant effects, which are possibly related to the selective blockade of NMDA receptor-associated ion-channels, resulting in increased glutamate release (18,19). ...
Opioid-induced hyperalgesia (OIH) is a condition of nociceptive sensitization caused by exposure to opioids, which is characterized by a paradoxical response whereby patients receiving opioids for the treatment of pain actually become more sensitive to pain as a direct result of opioid therapy. There is increasing evidence showing OIH presents a clinical challenge in acute, chronic, and cancer pain settings. Both clinical and animal studies have shown that glutamate N-methyl-D-aspartate (NMDA) receptors may play a key role in OIH, and pre-application of ketamine, an NMDA receptor antagonist, or a co-administration of ketamine and opioids, can prevent OIH. However, no reports have shown if ketamine can reverse OIH once it occurs. We present a case of a 56-year-old male with a past medical history of DM-2 with severe peripheral neuropathy, recurrent osteomyelitis of the left foot, hypertension, dyslipidemia, chronic neck and right arm pain due to cervical spondylosis, status post 4 times of cervical discectomy, and fusion surgeries for cervical radiculopathy. He was prescribed to high doses of opioids (morphine 60 mg, orally every 8 hours and hydrocodone/acetaminophen 10/325 mg, as needed up to 4 times daily) for approximately 10 years. He underwent left below-knee amputation due to uncontrolled osteomyelitis. The patient had worsening stump pain with an increasing dose of opioids and phantom pain on post-operative day one, and he developed OIH, diagnosed as escalating pain reports with every opioid dose increase. A ketamine infusion (loading dose of 10 mg IV bolus, then 20 mg/ hour IV infusion) was used after total cessation of opioid use for post-operative analgesia for 3 consecutive days and the patient recovered from his obvious OIH, with his stump pain and phantom pain well-controlled by opioid administration on post-operative day 5. In our case, the blockage of NMDA receptors by ketamine might quickly restore the balance between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems by deactivation of the latter, which may help the patient recover from OIH rapidly. While it is possible that ketamine may help facilitate patients’ recovery from OIH in addition to its ability to prevent OIH, this clinical observation must be tested in future prospective studies. Key words: Opioids, ketamine, opioid-induced hyperalgesia, phantom pain, post-amputation, post-operative
... In another randomized controlled study involving 160 pregnant women undergoing cesarean section with spinal anesthesia, five minutes after delivery, subjects receiving 0.25 mg/kg intravenous ketamine via bolus doses significantly reduced the requirement for analgesics and had fewer side effects caused by opioids, compared with those in control group receiving normal saline solution after delivery (13). Ketamine has also been successfully used in phantom pain (14)(15)(16) although a recent case report demonstrated lack of efficacy when ketamine is used for this purpose (17). In a randomized, double-blind and crossover study of twenty patients, ketamine (0.4 mg/kg, IV), but not calcitonin, was shown to reduce phantom limb pain (14), which was supported by a double-blind saline-controlled study in which 11 patients had decreased stumped and phantom limb pain scores as a response to ketamine (0.1 mg/kg/5 min IV bolus, followed by an infusion rate of 7 µg/kg/ min) (16). ...
... Ketamine has also been successfully used in phantom pain (14)(15)(16) although a recent case report demonstrated lack of efficacy when ketamine is used for this purpose (17). In a randomized, double-blind and crossover study of twenty patients, ketamine (0.4 mg/kg, IV), but not calcitonin, was shown to reduce phantom limb pain (14), which was supported by a double-blind saline-controlled study in which 11 patients had decreased stumped and phantom limb pain scores as a response to ketamine (0.1 mg/kg/5 min IV bolus, followed by an infusion rate of 7 µg/kg/ min) (16). Recently ketamine has been found to have antidepressant effects, which are possibly related to the selective blockade of NMDA receptor-associated ion-channels, resulting in increased glutamate release (18,19). ...
Opioid-induced hyperalgesia (OIH) is a condition of nociceptive sensitization caused by exposure to opioids, which is characterized by a paradoxical response whereby patients receiving opioids for the treatment of pain actually become more sensitive to pain as a direct result of opioid therapy. There is increasing evidence showing OIH presents a clinical challenge in acute, chronic, and cancer pain settings. Both clinical and animal studies have shown that glutamate N-methyl-Daspartate (NMDA) receptors may play a key role in OIH and pre-application of ketamine, an NMDA receptor antagonist, or co-administration of ketamine and opioids, can prevent OIH. However, no reports have shown if ketamine can reverse OIH once it occurs. We present a case of a 56-year-old male with past medical history of DM-2 with severe peripheral neuropathy, recurrent osteomyelitis of the left foot, hypertension, dyslipidemia, chronic neck and right arm pain due to cervical spondylosis, status post four times of cervical discectomy and fusion surgeries for cervical radiculopathy. He was on high doses of opioids (MS Contin 60 mg po q8 hour and hydrocodone/acetaminophen 10/325 prn- up to 4 times daily) for approximately 10 years. He underwent left below knee amputation due to uncontrolled osteomyelitis. The patient had worsening stump pain with increasing dose of opioids and phantom pain on post-operative day 1, and he developed OIH, diagnosed as escalating pain reports with every opioid dose increase. A ketamine infusion (loading dose 10 mg IV bolus, then 20 mg/hour IV infusion) was used after total cessation of opioid use for postoperative analgesia for 3 consecutive days and the patient recovered from his obvious OIH, with his stump pain and phantom pain well-controlled by opioid administration on post-operative day 5. In our case, blockage of NMDA receptors by ketamine might quickly restore the balance between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems by deactivation of the latter, which may help the patient recover from OIH rapidly. While it is possible that ketamine may help facilitate patients’ recovery from OIH in addition to its ability to prevent OIH, this clinical observation has to be tested in future prospective studies. Key words: Ketamin, opioid-induced hyperalgesia
... 41 Calcitonin therapy may reduce pain after surgery but is ineffective for persistent post-amputation pain issues. 42 Using the NMDA receptor antagonist Memantine to treat phantom limb pain also had ineffective results. 43 ...
Pain remains a very important issue that needs to be addressed after amputation of the lower limb. There are may pharmacological
agents available and many procedures which can be used to give pain relief to these patients but with varying degree of
acceptability and success.
The current review article discusses about the challenges related to the management of pain after amputation of lower limb
and recent trends in this field
... In the course of their therapy with memantine, five patients reported a somewhat elevated level of (mean at baseline: 46.98 20.38; with memantinee: 51.51 20.61). In a trial that was randomized, double-blind, and cross-over, Eichenberger et al. 27 examined the effects of ketamine intravenously (i.e.) with calcitonin, ketamine + calcitonin, and a placebo in 20 patients who had chronic PLP that was more than 3/11 on the VAS. The percent change in immediately after completing the treatments showed that calcitonin was no different than the placebo, while ketamine alone and in combination resulted in a significant reduction of on the VAS, compared to placebo and calcitonin (p< 0.05). ...
... Correll et al. lacks a control group which makes it difficult to determine the specific impact of the ketamine treatment as compared to other variables [22]. Eichenberger et al. had more males than females included in the study, and there was a wide range of chronic pain duration among the patients [23]. These factors may have affected the study findings. ...
Background
Chronic pain exerts a significant physical, emotional, and socioeconomic toll on millions of patients worldwide. Traditional pharmacological interventions are often inadequate in providing lasting and effective pain relief for patients suffering from severe chronic pain. However, in recent years, intravenous ketamine infusion therapy has emerged as a promising and alternative treatment modality. The effectiveness of intravenous ketamine infusion therapy in treating chronic pain has been investigated in various pain conditions, such as neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS), and phantom limb pain. However, varied patient demographics, different endpoints for measuring analgesia, and inconsistent numbers of patients in studies have led to conflicting results. The objective of the present inquiry is to undertake a contemporary updated meta‐analysis of the application of IV ketamine infusion therapy in the context of persistent pain.
Methods
A search was conducted, adhering to the PRISMA guidelines, to compare the efficacy of IV Ketamine infusion versus control (placebo, midazolam, gabapentin, hydromorphone, and pregabalin) among individuals with chronic pain. During the analysis, Medline, Cochrane, and Embase were thoroughly searched. Two independent investigators identified randomized double‐blind and non‐randomized trials comparing IV Ketamine infusions with controls. Review Manager 5.4.1 was used to scrutinize the data, with the main focus on pain scores. Secondary outcomes such as quality of sleep, as well as side effects such as nausea, hallucinations, and sedation, were also analyzed. Sixteen studies were included involving 1080 patients.
Results
The pain score was significantly reduced by IV Ketamine (Mean difference −1.05; 95% CI −1.72, −0.39; p = 0.002), while the quality of sleep (Mean difference 0.00; 95% CI −0.12, 0.12; p = 1.00) was not significantly different between studies. Nausea (risk ratio 1.42; 95% CI 0.84, 2.39; p = 0.19), hallucinations (risk ratio 1.08; 95% CI 0.67, 1.76; p = 0.75), and sedation (risk ratio 1.05; 95% CI 0.24, 4.54; p = 0.95) outcomes were not significantly different among the studies.
Conclusions
Our meta‐analysis indicates that IV Ketamine infusion is efficacious and safe in patients with chronic pain.
... Calcitonin is effective in acute phantom limb pain, but its has not been studied in the chronic phase. In a randomized, double-blind, crossover trial, intravenous infusions of calcitonin, ketamine (NMDA antagonist), and calcitonin combined with ketamine were tested against saline placebo in patients with phantom limb pain (Eichenberger et al 2008). ...
This report describes the latest concepts of pathomechanisms of pain as a basis for management and development of new pharmacotherapies for pain. Major segments of the pain market are arthritis, neuropathic pain and cancer pain. Because pain is a subjective sensation, it is difficult to evaluate objectively in clinical trials. Various tools for pain measurement are described, including brain imaging.
Most of the currently used analgesic drugs fall into the categories of opioids and nonsteroidal antiinflammatory drugs such as COX-2 inhibitors. Non-opioid analgesics include ketamine, a N-methyl-D-aspartate receptor antagonist. Adjuvant analgesics include antidepressants and antiepileptic drugs used for the treatment of neuropathic pain. Management of pain is multidisciplinary and includes both pharmacological and non-pharmacological methods such as acupuncture, transcutaneous electrical nerve stimulation and surgery. Various pain syndromes require different approaches in management, for example, the main category of drugs for migraine are triptans such as sumatriptan.
Drug delivery is an important consideration in pain treatment. Controlled release preparations provide a steady delivery of analgesics. Well-known non-injection methods such astransdermal, pulmonary and intranasal application have been used. Topical analgesics and local anesthetics are also available. Devices such as implanted pumps are used for delivery of drugs such as opioids intrathecally (introduction into spinal subarachnoid space by lumbar puncture) in patients with cancer pain.
The wide variety of drugs in development includes opioid receptor ligands, bradykinin antagonists, mPGES-1 inhibitors, glutamate receptor antagonists, substance P and neurokinin receptor antagonists, norepinephrine transporter inhibitors,P2X2 neuron receptor antagonists and nitric oxide-based analgesics. A number of cannabinoids are also in development for pain. Fish-derived tetrodotoxin was initially focused on indication of opiate addiction withdrawal but is found to have an analgesic action as well. Cone shells contain therapeutically useful peptides including the conotoxins, and one such peptide, ziconotide, has been approved. Various cell and gene therapies are also being developed for the management of pain.
Advances in molecular and biological techniques are markedly advancing our undestanding of pain. Understanding the pathophysiology of pain is an important factor in discovery of rational therapies for pain. Advances in pharmacogenomics and pharmacogenetics are enabling the development of personalized approaches to the management of pain.
Over 500 companies have been identified to be involved in developing or marketing pain therapeutics and 173 of these are profiled in the report along with 156 collaborations. These are a mix of pharmaceutical companies and biotechnology companies.
The worldwide analgesic markets were analyzed for the year 2020 and projected to 2030. Calculations are based on the epidemiology of various painful conditions and the development of analgesic drugs and devices. Unfulfilled needs for analgesics are identified and strategies are outlined to develop markets for analgesic drugs. The report is supplemented with 78 tables, 25 figures, and 600 selected references to the literature.
... A gold standard for PLP treatment is still lacking since several studies, including large surveys of patients with amputations, have shown that most treatments are ineffective (Griffin and Tsao, 2014). Available therapies include acupuncture, deep brain stimulation (Flor, 2002), mirror/virtual reality therapies (Chan et al., 2007;Mercier and Sirigu, 2009), mental imagery (MacIver et al., 2008), transcutaneous nerve stimulation (Katz and Melzack, 1991), deep brain, motor cortex, spinal cord, dorsal root ganglion and peripheral nerve stimulation (Krainick et al., 1980;Bittar et al., 2005;Ahmed et al., 2011), drugs such as carbamazepine, opioids (Wu et al., 2008), gabapentin (Bone et al., 2002), amitriptyline (Robinson et al., 2004), calcitonin (Jaeger and Maier, 1992), ketamine (Eichenberger et al., 2008) and memantine (Nikolajsen et al., 2000), local anaesthesia, sympathectomy, dorsal root entry-zone lesions, cordotomy and rhizotomy (see Sherman et al., 1980;Sherman, 1997). ...
... Outcome measures such as Two -point discrimination (TPD) threshold is of interest to the target population as it allows the exploration of changes in sensorimotor/samotosensory function, which is purported to be the key mechanism for change in SDT. (Kulunkoglu et al., 2019), (Ol et al., 2018), (Finn et al., 2017), (Malavera et al., 2016), (Tilak et al., 2016), (Karanikolas, 2011), (Ahmed et al., 2011), (Casale et al., 2009) (Ulger et al., 2009), (Eichenberger et al., 2008) (Chan BL, 2007), (Brodie et al., 2007), (Moseley, 2006), (Wu et al., 2012), (Wiech et al., 2004), (Wu et al., 2002), NRS for pain Intensity of Pain (Hsiao et al., 2012), (Moseley, 2006), (Bokkon et al., 2011), (Kern et al., 2006), , (Smith et al., 2005) (Maier et al., 2003) MPQ, SF-MPQ or SF-MPQ-2 Intensity of pain -individual descriptors (Ramadugu et al., 2017b), (Karanikolas, 2011), (Brodie et al., 2007), (Moseley, 2006), , (E. ...
Introduction:
Phantom limb pain (PLP) is intractable to treatment. Sensory discrimination training (SDT) is a non-pharmacological treatment, which shows potential promise for PLP, but robust clinical trials are lacking. This thesis aimed to develop a robust RCT protocol to investigate the efficacy of an automated, self-management SDT device (SP1X) for the treatment of PLP.
Methods:
Three studies contributed to the development of an RCT protocol to investigate the efficacy of SP1X. Firstly, a qualitative study explored participants perceptions of PLP self-management. Secondly, a systematic review investigated the efficacy and safety of SDT for chronic musculoskeletal pain conditions. Thirdly, a measurement study investigated the psychometric properties of key outcome measures for use with the PLP population.
Results:
Participants experiences of self-management of PLP were positive highlighting self-management as an acceptable and feasible approach. The systematic review found SDT does not appear to be associated with any adverse effects and shows potential regarding its clinical efficacy. However, high-quality evidence upon which to make firm clinical recommendations was lacking. The measurement study found three outcome measures for pain intensity, and one for quality of life, possessed acceptable psychometric properties for use in future research trials. Two sensorimotor outcome measures required further development and subsequent psychometric testing prior to use in future research trials.
Conclusions and implications:
Self-management strategies are an acceptable and feasible approach that could be incorporated into the lives of people with PLP. SDT has the potential to be safe and effective for PLP. Existing outcome measures for pain are sufficiently reliable for use in PLP research but should be interpreted cautiously on an individual patient level. This thesis developed a robust protocol to investigate the efficacy of SP1X. The protocol now needs to be undertaken to investigate the efficacy of SP1X before any recommendations on its use can be made.
... In randomized controlled, double-blind studies, ketamine was found to provide better pain relief than placebo in subjects with mixed neuropathic pain; however, this improvement was often short in duration and inconsistent across trials (67)(68)(69). Similar trials in subjects with traumatic spinal cord injury, phantom limb pain, or postherpetic neuralgia show similar improvements, though often not demonstrating long-lived effects (70)(71)(72). ...
The phencyclidine-derivative ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one] was added to the World Health Organization's Model List of Essential Medicines in 1985 and is also on the Model List of Essential Medicines for Children due to its efficacy and safety as an intravenous anesthetic. In sub-anesthetic doses, ketamine is an effective analgesic for the treatment of acute pain (such as may occur in the perioperative setting). Additionally, ketamine may have efficacy in relieving some forms of chronic pain. In 2019, Janssen Pharmaceuticals received regulatory-approval in both the United States and Europe for use of the S-enantiomer of ketamine in adults living with treatment-resistant major depressive disorder. Pre-existing anxiety/depression and the severity of postoperative pain are risk factors for development of chronic postsurgical pain. An important question is whether short-term administration of ketamine can prevent the conversion of acute postsurgical pain to chronic postsurgical pain. Here, we have reviewed ketamine's effects on the biopsychological processes underlying pain perception and affective mood disorders, focusing on non-NMDA receptor-mediated effects, with an emphasis on results from human trials where available.
... BTx-A Blocks presynaptic cholinergic receptors Reduced TRPV1 and sodium channel activity Reduced local/central inflammation Hypersensitivity Edema, injection site pain Very weak evidence [64,65] Hormones Calcitonin (intravenous/ epidural) Inhibits neuronal firing in response to peripheral stimulation Inconclusive, conflicting results for IV, [66,67] weak evidence of preventive epidural calcitonin [68] attempted based on the altered neurophysiology in phantom limb patients. ...
Postamputation phenomenon is commonly encountered in more than 80% of amputees. Due to the increasing burden of trauma and associated amputations, disability due to postamputation pain becomes rampant. In this review, we aim to describe the history, epidemiology, types and mechanisms of postamputation phenomenon, factors affecting its development, and the currently available treatment modalities – both pharmacological and nonpharmacological.
... Outpatient ketamine has been studied for chronic neuropathic pain states, including postherpetic neuralgia [53], complex regional pain syndrome (CRPS) [54], cancer pain [55,56], orofacial pain [57] and phantom limb pain [58] in various small studies, most of which were descriptive in the form of case series and reports. Routes of administration include intravenous (IV), subcutaneous, oral, intranasal, and transdermal. ...
Purpose of Review
Many surgical subspecialties have developed enhanced recovery after surgery (ERAS) protocols that focus on multimodal analgesia to limit opioid use during a hospital stay and improve patient recovery. Unfortunately, ERAS protocols do not extend to post-discharge patient care, and opioids continue to be over prescribed. The primary reason seems to be a lack of good quality research evaluating extended use of a multimodal analgesic approach. This review was undertaken to evaluate available evidence for non-opioid analgesics in the postoperative period after discharge, utilizing Pubmed, Scopus, and Google Scholar.
Recent Findings
Several studies have explored strategies to reduce the overprescribing of opioids after surgery without worsening postoperative pain scores or complications. However, these studies do not necessarily reflect on situations where an ultra-restrictive protocol may fail, leading to breakthrough pain. Ultra-restrictive opioid protocols, therefore, could risk undertreatment of acute pain and the development of persistent post-surgical pain, highlighting the need for a review of non-opioid strategies.
Summary
Our findings show that little research has been conducted on the efficacy of non-opioid therapies post-discharge including acetaminophen, NSAIDs, gabapentin, duloxetine, venlafaxine, tizanidine, valium, and oral ketamine. Further studies are warranted to more precisely evaluate the utility of these agents, specifically for their side effect profile and efficacy in improving pain-control and function while limiting opioid use.
... However, only the combination of ketamine and calcitonin improved average and peak pain intensity 48-hours after treatment. 74 These results support the administration of ketamine infusions for the reduction of phantom limb pain. ...
Chronic pain significantly worsens the quality of life. Unlike neuropathic, musculoskeletal, postoperative pain, and cancer pain, chronic primary pain cannot be explained by an underlying disease or condition, making its treatment arduous.
This manuscript intends to provide a comprehensive review of the use of ketamine as a treatment option for specific chronic pain conditions.
Study design is a review article. A search was done on PubMed for relevant articles.
A comprehensive review of the current understanding of chronic pain and the treatment of specific chronic pain conditions with ketamine.
Literature is scarce regarding the use of ketamine for the treatment of chronic pain.
First-line treatment for many chronic pain conditions includes NSAIDs, antidepressants, anticonvulsants, and opioids. However, these treatment methods are unsuccessful in a subset of patients. Ketamine has been explored in randomized controlled trials (RCTs) as an alternative treatment option, and it has been demonstrated to improve pain symptoms, patient satisfaction, and quality of life. Conditions highlighted in this review include neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS), phantom limb pain (PLP), cancer pain, and post-thoracotomy pain syndrome. This review will discuss conditions, such as neuropathic pain, fibromyalgia, complex regional pain syndrome, and more and ketamine’s efficacy and its supplementary benefits in the chronic pain patient population. As the opioid crisis in the United States continues to persist, this review aims to understand better multimodal analgesia, which can improve how chronic pain is managed.
... Ketamine is efficacious in a variety of chronic pain conditions such as Complex Regional Pain Syndrome (CRPS) [9] [10], spinal cord injury pain [11], fibromyalgia [12], peripheral neuropathic pain [13] [14], phantom limb pain [15], postherpetic neuralgia [16] and opioid-induced hyperalgesia [17] [18]. ...
... In a study by Eichenberger et al., 24 it was shown that ketamine infusion alone had a greater effect on phantom pain control of the extremities rather than calcitonin infusion, but infusion of both drugs had a significant effect on pain control. Based on a study by Papadokostakis et al., 25 it was observed that nasal injection of calcitonin can have an effect on the control of chronic low back pain in patients with osteoporosis. ...
Objective:
Back pain is reported to be the fifth most common reason for referral a patient to a physician and the most common disability in modern society. The present study aimed to evaluate the effects of calcitonin addition on epidural injection in patients with degenerative spinal canal stenosis in comparison with epidural triamcinolone injection.
Materials and methods:
The clinical trial study was performed on 40 patients with degenerative spinal stenosis, referred to pain clinic of RasoulAkram Hospital in 2018, who were randomly divided into two intervention and control groups, including 20 individuals in each group. In the intervention group, 50 units of calcitonin were injected with 8 cc of ropivacaine 0.2% while 80 mg of triamcinolone with 8 cc of ropivacaine 0.2% was injected in the control group. Functional disability was evaluated based on the Oswestry Disability Index (ODI) and pain ratings were assessed using the Visual Analogue Scale (VAS).
Results:
Pain at 4 and 8 weeks after the procedure was significantly different between the two groups. A significant difference in the patient disability index was observed between two groups at 8 and 12 weeks after the procedure. On the other hand, the rate of analgesic consumption at 4, 8 and 12 weeks after the procedure was significantly decreased in the calcitonin group (P <0.001).
Conclusions:
Based on our results, injection of calcitonin into the epidural space can reduce the pain of the patients and their analgesic consumption compared to the group receiving steroids through the epidural space.
... Opioids (levorphanol, oxycodone, methadone, and morphine) provide analgesia without causing the loss of proprioception, touch, or consciousness by binding to peripheral and central opioid receptors. Calcitonin can also be used for PLP, but its therapeutic effect is mixed and the mechanism is unclear [14,15]. ...
Phantom limb pain (PLP) is a common complaint among patients after amputation, while jumping residual limb is a rare post-amputation complication, they rarely happen at the same time and both remain difficult to manage. At present, there is a paucity of literature on this topic, and no treatment has been proven effective for treating both of them. In the present brief report, we described a patient who developed severe PLP accompanied by jumping residual limb after below-the-knee amputation and she was treated by auricular therapy (AT) with satisfactory effect.
... In addition to its use in treating acute pain, ketamine is also used in chronic pain syndromes, where it exerts beneficial effects through the inhibition of NMDARs [50]. Ketamine has been suggested to be effective in treating many different types of chronic pain, such as neuropathic pain [51] and phantom limb pain [52,53], cancer pain [54], and migraine with prolonged aura [55]. Ketamine may be particularly useful in instances where opioids no longer provide sufficient pain relief because it has been suggested to reduce opioid tolerance and pain hypersensitivity [56,57]. ...
Over the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine’s effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine’s complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine’s rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine’s action.
... El papel terapéutico de la calcitonina es mixto, y sus mecanismos en el tratamiento del DMF son inciertos 55,50 . La infusión iv de calcitonina ha mostrado capacidad preventiva 42 y terapéutica del DMF con reducción del dolor en el seguimiento a un año 56 . ...
INTRODUCCIÓN La primera descripción de Dolor de Miembro Fantasma (DMF) se realizó en 1552 por el cirujano barbero Ambroise Paré, pero el término actual lo acuñó en 1866 el neurólogo Si-las Weir Mitchell, que atendió muchos pacientes amputados durante la guerra de Secesión Norteamericana 1. La International Association for the Study of Pain (IASP) define el DMF como "dolor referido a una extremidad amputada total o parcialmente" 2. Se trata de una modalidad de dolor neuropático crónico que sufren el 45-85% de los pacientes que se someten a una amputación mayor de miembro superior o inferior, y produce discapacidad en cerca de dos tercios de los amputados 3, 4. El dolor de muñón (DM) es el que se produce en la región restante de la extremidad amputada, y sensación de miembro fantasma (SMF) es la producida en la parte del cuerpo que ya no existe. También puede darse en la mastectomía, especialmente si esta se realiza antes de la menopausia 2. AMPUTACIONES La causa principal de amputación de miembro inferior en EEUU es la enfermedad vascular periférica (54%) incluyendo diabetes y enfermedad arterial periférica, trauma (45%) y cáncer (menos del 2%), mientras que las de miembro superior son trauma (77%), ausencia congénita de miembro superior, y tumores (6%) 5. En España se realizan más de 5.000 amputaciones mayores de extremidad inferior (AMEI) anualmente, 57% en pacientes con diabetes tipo 2 6. *
Este capítulo debe referenciarse como: CID CALZADA J, PARRA JAREÑO R, GÓMEZ-CARO ÁLVAREZ-PALENCIA L, MAREQUE ORTEGA M, ROMEROSA MARTÍNEZ B. Dolor de miembro fantasma. Opciones de tratamiento: ¿Existe un algoritmo clínico? En: J. De Andrés (editor). Puesta al día en Anestesia Regional y Tratamiento del Dolor. Vol XXI. ISSN 1578-5580. Barcelona. Editorial MRA; 2018. p. 609-641.
... In diesem Zusammenhang ist möglicherweise eine Studie zu abdominalchirurgischen Patienten interessant [3], die in ähnlich niedriger Dosierung von 0,015 mg/kgKG je h eine gute analgetische Wirksamkeit erreichte, in der auch im Verlauf auf der Normalstation keine psychodysleptischen Nebenwirkungen auftraten. Insgesamt scheint die aus der Phantomschmerzbehandlung bekannte Applikation von Ketamin [10] auch für die Phantomschmerzprävention einen Stellenwert zu haben, der weiterer konfirmatorischer Studien bedarf. ...
Prevention of phantom limb pain is one of the biggest and still largely unsolved challenges in perioperative medicine. Despite many study efforts and optimization of postoperative pain treatment over the last 30 years, a significant reduction in the incidence of phantom limb pain has not been achieved. Current studies have also shown that at least 50% of patients develop phantom pain after 6 months. A possible approach could be to combine multiple synergistic interventions and implement them as a perioperative phantom pain management strategy bundle. In addition to regional anesthesia, NMDA antagonists, gabapentinoids, antidepressants and systemic lidocaine could play a relevant role. The aim of this pharmacological intervention was the modification of the pathophysiological changes in peripheral nerves and in the central nervous system after amputation.
... These medications are thought to block the hyper-excitability and sensitization mechanisms of PAP. 14,15 Intravenous ketamine has been shown to improve such pain in the short-term, while a small case series has also demonstrated potential benefit for the use of oral ketamine. 16 It is important to note that ketamine has side effects ranging from alterations in mood to hallucinations, and it is a highly abusable drug. ...
Introduction:
The prevalence of amputation and post-amputation pain (PAP) is rising. There are two main types of PAP: residual limb pain (RLP) and phantom limb pain (PLP), with an estimated 95% of people with amputations experiencing one or both. Medical Management: The majority of chronic PAP is due to phantom limb pain, which is neurogenic in nature. Common medications used include tricyclic antidepressants, gabapentin, and opioids. Newer studies are evaluating alternative drugs such as ketamine and local anesthetics. Rehabilitation Management: Mirror visual feedback and cognitive behavioral therapy are often effective adjunct therapies and have minimal adverse effects. Surgical Management: Neuromodulatory treatment and surgery for neuromas have been found to help select patients with PAP.
Conclusion:
PAP is a complex condition with mechanisms that can be located at the residual limb, spinal cord, and brain - or a combination. This complex pain can be difficult to treat. The mainstays of treatment are largely medical, but several surgical options are also being studied.
Background/importance
Neuropathic amputation-related pain can consist of phantom limb pain (PLP), residual limb pain (RLP), or a combination of both pathologies. Estimated of lifetime prevalence of pain and after amputation ranges between 8% and 72%.
Objective
This narrative review aims to summarize the surgical and non-surgical treatment options for amputation-related neuropathic pain to aid in developing optimized multidisciplinary and multimodal treatment plans that leverage multidisciplinary care.
Evidence review
A search of the English literature using the following keywords was performed: PLP, amputation pain, RLP. Abstract and full-text articles were evaluated for surgical treatments, medical management, regional anesthesia, peripheral block, neuromodulation, spinal cord stimulation, dorsal root ganglia, and peripheral nerve stimulation.
Findings
The evidence supporting most if not all interventions for PLP are inconclusive and lack high certainty. Targeted muscle reinnervation and regional peripheral nerve interface are the leading surgical treatment options for reducing neuroma formation and reducing PLP. Non-surgical options include pharmaceutical therapy, regional interventional techniques and behavioral therapies that can benefit certain patients. There is a growing evidence that neuromodulation at the spinal cord or the dorsal root ganglia and/or peripheral nerves can be an adjuvant therapy for PLP.
Conclusions
Multimodal approaches combining pharmacotherapy, surgery and invasive neuromodulation procedures would appear to be the most promising strategy for preventive and treating PLP and RLP. Future efforts should focus on cross-disciplinary education to increase awareness of treatment options exploring best practices for preventing pain at the time of amputation and enhancing treatment of chronic postamputation pain.
Rationale. Despite a large number of studies on the effectiveness of various pharmacological and non- pharmacological therapies, PLP treatment tactics have not yet been developed, which is largely due to the complex mechanism of the formation of this pathology. Although PLP is classified as neuropathic pain, standard methods of neuropathic pain therapy are not always effective for this syndrome. To optimize the regimens of existing methods of PLP treatment, as well as the search and clinical trials of new therapeutic approaches, it is necessary to take into account the currently available evidence base.
Material and methods. Our analysis included publications on phantom pain treatment methods with a high level of evidence (randomized controlled trials, systematic reviews and meta-analyses). Literature search was performed in Medline PubMed and eLIBRARY systems.
Results. The review provides an evidence base for pharmacotherapy methods (opioids, NMDA-receptor antagonists, tricyclic antidepressants, anticonvulsants, local anesthetics), for methods based on the phantom illusion (mirror therapy, motion representation, virtual reality), for non-invasive (transcutaneous electrical neurostimulation, transcranial magnetic stimulation, transcranial electrical stimulation) and invasive (deep brain stimulation, motor cortex stimulation, spinal cord stimulation, dorsal root ganglion stimulation) neuromodulation. Data on the most studied dosing regimens of different methods of pharmacological and non-pharmacological therapy are presented.
The practice of pain medicine has changed dramatically over the past few years. This practical and accessible evidence-based clinical handbook provides medical and nursing professionals with in-depth and up-to-date information on the various types of chronic pain, the underlying causes, and associated symptoms. Focused primarily on the management of chronic pain, the book covers the major chronic pain conditions in the head and neck, spine, and extremities. Also, it provides invaluable guidance on various pain management techniques, including medication, physical therapy, and psychological interventions. With this knowledge, healthcare professionals will be equipped to provide more effective and compassionate care, improve patients' quality of life, and reduce the risk of chronic pain and opioid dependence. An invaluable resource for pain medicine physicians, anesthesiologiests, primary care physicians, emergency medicine physicians, and nurse anaesthetists as well as those physicians preparing for US Board certification and recertification exams.
Introduction
Fibromyalgia is a complex disorder characterized by distributed and persistent pain often associated with fatigue and depression. The underlying causal agents of this dysfunction are not clear. Ketamine has been used to treat chronic pain in a variety of pain syndromes, including fibromyalgia, but the dosing protocols used are neither standardized nor consistent across cases. The current case presents an opportunity to contribute to a progression towards a consensus on ketamine dosing for fibromyalgia.
Case Presentation
A 60-year-old female presented with indications of fibromyalgia and was administered a 9-session IV ketamine treatment for pain. The initial dosing was 50 mg, with a concentration of 1.0 mg/ml at an infusion rate of 0.8 mg/kg/hr. This was increased to 200 mg and eventually to 240 mg, maintaining a ketamine concentration 4.0–4.8 mg/ml at an infusion rate of 1.5 mg/kg/hr.
Management and Outcomes
Following the first 9-session therapy, the patient reported >50% pain relief from pre-infusion levels and was placed on a maintenance regimen in perpetuity. This regimen involves two monthly IV ketamine infusions, one day apart for two hours at a maintenance rate of 4.8 mg/kg/hr.
Conclusion
Ketamine by IV is an effective option for pain management in patients with fibromyalgia. Compared to previous case studies, it is recommended that increased total dose, frequent administration, and longer duration of infusions all may be necessary for ketamine to maximize its beneficial effects.
Phantom limb pain is a specific entity of neuropathic pain that develops in 30%85% of patients with amputated limbs and leads to considerable worsening of the quality of life. The number of such cases increases during military conflicts. It can be caused by a traumatic amputation due to mine blast injury, peculiarities of provided medical assistance, and the special psychological state of casualties being in extremely stressful situations at the moment of wounding. Phantom limb pain development is accompanied by multiple functional and structural changes at different levels of the peripheral and central nervous systems. As a result, different theories of pathogenesis are proposed. However, at present, no final opinion concerns mechanisms of phantom limb pain development. Although different versions of drug and non-drug therapy have been suggested, none of them turned out to be universal and fully effective. Many medications were found to be linked to phantom limb pain pathogenesis; however, even first-line therapy drugs (non-steroidal anti-inflammatory drugs, tricyclic antidepressants, narcotic analgesics, and anticonvulsants) often fail to provide adequate analgesia. Long-term prescription of narcotic analgesics is at risk of the development of addictive disorders. Surgical interventions have not demonstrated their effectiveness as well. Thus, their use is justified only in the case of ineffective conservative treatment. Poor efficacy of conventional concepts of phantom limb pain treatment led to the use of new means such as botulinum toxin therapy, non-drug methods (psychotherapy, mirror therapy, biological feedback, virtual reality, acupuncture, massage, hypnosis, etc.). Thus, the search for original methods based on the development and introduction of new drug therapy schemes is imperative. A possible solution to this problem is not only creating absolutely new non-opioid analgesics but also using adjuvant therapeutic means in the multimodality schemes of analgesia. The latter promotes neurotransmission in the antinociceptive system and potentiates the effect of traditional analgesics.
Objective: Painful Phantom Limb Syndrome (PPLS) occurs in 50 to 80% of patients undergoing amputation, having a great impact on quality of life, productivity and psychosocial sphere. The objective of this review is to summarize the pharmacological and non-pharmacological strategies, surgical optimization, and provide a multidisciplinary approach aimed at reducing the incidence of chronic pain associated with PPLS in patients undergoing limb amputation.
Methods: A narrative review was carried out using Medline, Pubmed, Proquest, LILACS and Cochrane, searching for articles between 2000 and 2021. Articles describing the epidemiology, pathophysiological considerations, and current treatments were selected after a screening process.
Results: A multidisciplinary and multimodal approach is required in PPLS, and should include the use of regional techniques, and adjuvants such as NSAIDs, ketamine, lidocaine and gabapentinoids. In addition, an evaluation and continuous management of risk factors for chronic pain in conjunction with the surgical team is necessary.
Conclusion: The current literature does not support that a single technique is effective in the prevention of PPLS. However, adequate acute pain control, rehabilitation and early restoration of the body scheme under a multidisciplinary and multimodal approach have shown benefit in the acute setting.
Chronic pain begins with acute pain. Physicians tend to classify pain by duration (acute vs chronic) and mechanism (nociceptive, neuropathic and nociplastic). Although this taxonomy may facilitate diagnosis and documentation, such categories are to some degree arbitrary constructs, with significant overlap in terms of mechanisms and treatments. In clinical practice, there are myriad different definitions for chronic pain and a substantial portion of chronic pain involves mixed phenotypes. Classification of pain based on acuity and mechanisms informs management at all levels and constitutes a critical part of guidelines and treatment for chronic pain care. Yet specialty care is often siloed, with advances in understanding lagging years behind in some areas in which these developments should be at the forefront of clinical practice. For example, in perioperative pain management, enhanced recovery protocols are not standardized and tend to drive treatment without consideration of mechanisms, which in many cases may be incongruent with personalized medicine and mechanism-based treatment. In this educational document, we discuss mechanisms and classification of pain as it pertains to commonly performed surgical procedures. Our goal is to provide a clinical reference for the acute pain physician to facilitate pain management decision-making (both diagnosis and therapy) in the perioperative period.
Objective:
To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on phantom limb pain (PLP) in amputees, and to compare the therapeutic effect with that of mirror therapy (MT).
Methods:
The study was designed as a randomized controlled trial. The evaluators were blinded, while the subjects and the therapists were unblinded. Subjects were randomly assigned to either the rTMS group or the MT group with a computer-generated random number table. From June 2018 to December 2020, from out of 45 amputee patients screened for the study, 30 who met the inclusion criteria were recruited for the study. All patients were recruited from the Rehabilitation Medicine Center, West China Hospital, Sichuan University. In the end, 4 patients withdrew from the study and 26 patients (12 in the rTMS group and 14 in the MT group) completed the prescribed treatment and evaluation. The rTMS group was given rTMS (1 Hz, 15 min, 5 d/week) for 2 weeks in addition to conventional rehabilitation therapy, while the MT group received MT (corresponding movements of limbs, 15 min, 5 d/week) for 2 weeks in addition to conventional rehabilitation therapy. PLP was evaluated by the Visual Analogue Scale (VAS) and Douleur Neuropathique 4 Questions (DN-4). Subjects were assessed before treatment ( t 0), immediately after the completion of the treatment ( t 1) and 3 months after the completion of the treatment ( t 2).
Results:
The mean age of the 26 patients was 39.73±12.64. There were 15 males and 11 females. According to the reported description of the characteristics of the PLP by the patients, the characteristics with the highest incidence were tingling, stabbing, numbing, electric shocks and burning in descending order. There was no significant difference in the incidence of PLP characteristics between the two groups ( P>0.05). The two groups had comparable baseline data, showing no significant difference in VAS and DN-4 between the two groups at t 0 ( P>0.05). At t 1 and t 2, the VAS and DN-4 scores were decreased from those of t 0, showing statistically significant difference in both groups ( P<0.01 for both scores). In the rTMS group, there was no significant difference between VAS and DN-4 scores at t 1 and those at t 2 ( P>0.05). In the MT group, the VAS and DN-4 scores at t 2 were significantly lower than those of t 1 ( P<0.05). There was no statistically significant difference between the rTMS group and MT group in the changes in pain measurements, i.e., VAS and DN-4 scores, before and after the intervention ( P>0.05). The 26 patients who completed the experiment showed no dizziness, headache, or other abnormalities during the study.
Conclusion:
The results of this study indicate that repetitive transcranial magnetic stimulation could improve PLP in amputees, and the improvement effect was comparable to that of mirror therapy.
Introduction:
Most patients with amputation (up to 80 %) suffer from phantom limb pain postsurgery. These are often multimorbid patients who also have multiple risk factors for the development of chronic pain from a pain medicine perspective. Surgical removal of the body part and sectioning of peripheral nerves result in a lack of afferent feedback, followed by neuroplastic changes in the sensorimotor cortex. The experience of severe pain, peripheral, spinal, and cortical sensitization mechanisms, and changes in the body scheme contribute to chronic phantom limb pain. Psychosocial factors may also affect the course and the severity of the pain. Modern amputation medicine is an interdisciplinary responsibility.
Methods:
This review aims to provide an interdisciplinary overview of recent evidence-based and clinical knowledge.
Results:
The scientific evidence for best practice is weak and contrasted by various clinical reports describing the polypragmatic use of drugs and interventional techniques. Approaches to restore the body scheme and integration of sensorimotor input are of importance. Modern techniques, including apps and virtual reality, offer an exciting supplement to already established approaches based on mirror therapy. Targeted prosthesis care helps to obtain or restore limb function and at the same time plays an important role reshaping the body scheme.
Discussion:
Consequent prevention and treatment of severe postoperative pain and early integration of pharmacological and nonpharmacological interventions are required to reduce severe phantom limb pain. To obtain or restore body function, foresighted surgical planning and technique as well as an appropriate interdisciplinary management is needed.
This chapter reviews preclinical, clinical and other information regarding the rationale, practice and future directions of combination pharmacotherapy for chronic noncancer pain with the exclusion of headache. Chronic pain conditions often feature sensory hyperexcitability that manifests as hyperalgesia and allodynia. As one of several treatment modalities for chronic pain, drug therapy is often ineffective in a substantial proportion of patients and only partially effective in another patient subgroup. Providing the optimal balance between beneficial and adverse drug effects is central to optimizing outcomes with combination pharmacotherapy. Emphasizing the combination of analgesic agents that have the best possible efficacy and safety is perhaps the first, and most intuitive, principle of optimal combination therapy. Widespread use of combination pharmacotherapy in pain management reflects the current limitations of various available pharmacotherapies and, furthermore, emphasizes the need for combination‐specific research to distinguish between beneficial versus.
Background:
There is no recommendation in Europe for the use of ketamine in patients with chronic pain. The heterogeneity of practice highlights the need to seek the advice of experts in order to establish a national consensus. This Delphi survey aimed to reach a national consensus on the use of ketamine in chronic pain in Pain clinics.
Methods:
A collaborative four-round internet-based questionnaire was used. It was created after literature search on ketamine administration in chronic pain and included about 96 items. It discussed utility and advantages, adverse events and deleterious aspects, methods of administration, concomitant treatments and assessment of results.
Results:
Twenty-eight experts completed all rounds of the survey with a total of 81.3% items reaching a consensual answer. Neuropathic pain represents the first indication to use ketamine, followed, with a good to moderate utility, by other situations (fibromyalgia, complex regional pain syndrome, central neuropathic pain, peripheral neuropathic pain, nociceptive pain, sensitization, opioid withdrawal, palliative care, depression). Experts agreed on the rare occurrence of adverse events. Concerning routes of administration, intravenous infusion with doses of 0.5-0.9mg/kg/d for four days of treatment is preferred. Place of care is hospital, as in- or out-patient, with a quarterly administration of ketamine. Finally, ketamine effectiveness is assessed one month after infusion, and experts encourage combination with non-pharmacological treatment.
Conclusions:
This Delphi survey established a consensus of pain specialists on the use of ketamine in refractory chronic pain, thus providing a basis for future comparative trials.
Significance:
This Delphi survey in chronic pain reached agreement on 4 main aspects: 1) Priority to treat neuropathic pain with evaluation of effectiveness at 1 month; 2) No deleterious effects in the majority of listed diseases/situations with the absence or < 3% of suggested adverse events; 3) 0.5-0.9mg/kg/d IV infusion; 4) Combination with non-pharmacological treatment.
Injury to the nerves causes alteration in normal neurobiological sequences lead to disease of somatosensory nervous system called as neuropathic pain (NP). It affects both central as well as peripheral nervous system. It is a chronic painful condition occurs due to various diseases like HIV, diabetes, lesions, infection, trauma, and metabolic insults. NP affects 7-10% of global population, hence subsequently is a major concern. Pharmacotherapy for NP remains a major clinical challenge due to its complex pathophysiology. Current treatments like Analgesics, anticonvulsants, non-steroidal anti-inflammatory drugs, tri-cyclic antidepressants, sodium channel blocker and opioid agonist administrated individually to patients of NP are providing only meager and partial relief. Furthermore, these drugs have limited efficacy as well as adverse effects. Hence instead of monotherapy, pathophysiology of NP suggests that administering multiple drugs (polypharmacy) show quick and sufficient effect in the treatment of NP. Recent updates indicate that combination of Morphine and gabapentin, Pregabalin and duloxetine, Gabapentin and nortriptyline, Amitriptyline and ketamine (topical), Doxepin and capsaicin (topical), Glyceryl trinitrate (topical) and valproate are also a good choice for the treatment of NP. Several clinical trials also established that combination pharmacotherapy showed greater efficacy than monotherapy in treating NP. Physicians, scientists working in the area of NP are not only looking for its treatment but also in resolving the issues of co-morbidities associated with it. Hence the present review focuses on rationalized approach of combination therapy for the treatment of various aspects of NP.
Introduction:
Most patients with amputation (up to 80%) suffer from phantom limb pain postsurgery. These are often multimorbid patients who also have multiple risk factors for the development of chronic pain from a pain medicine perspective. Surgical removal of the body part and sectioning of peripheral nerves result in a lack of afferent feedback, followed by neuroplastic changes in the sensorimotor cortex. The experience of severe pain, peripheral, spinal, and cortical sensitization mechanisms, and changes in the body scheme contribute to chronic phantom limb pain. Psychosocial factors may also affect the course and the severity of the pain. Modern amputation medicine is an interdisciplinary responsibility.
Methods:
This review aims to provide an interdisciplinary overview of recent evidence-based and clinical knowledge.
Results:
The scientific evidence for best practice is weak and contrasted by various clinical reports describing the polypragmatic use of drugs and interventional techniques. Approaches to restore the body scheme and integration of sensorimotor input are of importance. Modern techniques, including apps and virtual reality, offer an exciting supplement to already established approaches based on mirror therapy. Targeted prosthesis care helps to obtain or restore limb function and at the same time plays an important role reshaping the body scheme.
Discussion:
Consequent prevention and treatment of severe postoperative pain and early integration of pharmacological and nonpharmacological interventions are required to reduce severe phantom limb pain. To obtain or restore body function, foresighted surgical planning and technique as well as an appropriate interdisciplinary management is needed.
Typical post amputation phenomena are stump pain (pain in the residual limb), phantom sensation and phantom limb pain. Of these, phantom sensation is ubiquitous, diminishes over time and cannot be treated. Stump pain can have multiple causes and requires careful assessment and targeted therapy depending on the causal diagnosis. Phantom limb pain occurs in 60–80% of all amputees and is the result of complex processes in the damaged peripheral nerves and the CNS. The most relevant risk factors are preoperative pain in the limb as well as psychological factors (such as depression and catastrophising) and severe pain in the early postoperative phase. A considerable number of preventive and therapeutic strategies are discussed, but the evidence for most of these is weak. As with all chronic pain states, a combination of pharmacological and non-pharmacological approaches to management should be utilised.
Chronic pain related to painful medical diseases is an extensive field that requires more awareness and large clinical research trials into optimal treatments that can increase patient satisfaction and quality of life. Using a multidisciplinary approach requires an array of medications, in addition to behavioral/psychological, interventional, and physical therapy treatments. Multimodal therapy through various medications described in this chapter is also essential to creating a balanced treatment plan that reduces risk and side effects from any single agent, especially opioids. The opioid epidemic is no doubt prevalent at this time, and recent guidelines reinforce the need for improved patient and physician education and access to safer and more effective options. When opioids are essential for certain medical conditions, increased awareness of long-term side effects and associated comorbidities can optimize the balance between risks and benefits.
Objetivo. Realizar revisão sistemática da literatura sobre as possíveis condutas farmacológicas utilizadas para tratamento da dor do membro fantasma. Método. A estratégia de busca foi realizada nas bases de dados eletrônicas Cochrane, Pubmed e Lilacs através da consulta de descritores específicos. A busca consistiu de artigos apresentados na íntegra, escritos em inglês ou espanhol, adultos humanos de ambos os sexos, publicados no período de 1990 a 2012. Resultados. Após a aplicação dos critérios de exclusão, foram selecionados 20 artigos. Através da análise, verificou-se que existem possibilidades terapêuticas positivas a curto prazo a serem utilizadas, dentre elas destacam-se os opióides, gabapentina e a quetamina. A morfina (oral e intravenosa) foi eficaz na diminuição da intensidade da dor a curto-prazo. Com exceção da memantina, os antagonistas do receptor NMDA, morfina e a quetamina apresentaram efeitos analgésicos. Entretanto, os resultados obtidos com a gabapentina em termos de alívio da dor não foram significativos. O direcionamento da eficácia da calcitonina e dextrometorfano necessitam maiores esclarecimentos. Conclusão. A morfina e a quetamina demonstraram ser eficazes como analgésicos de curta duração. Maiores estudos tornam-se necessários para esclarecer os reais benefícios da amitriptilina, o cloridrato de tramadol, memantina e a toxina botulínica. Intervenções em pesquisas com maior número de participantes são importantes, a fim de estabelecer recomendações na prática terapêutica.
The Chronic pain epidemic is a pressing public health crises facing the United States. Currently, more than 100 million Americans suffer from chronic pain, with chronic pain being among the most prevalent conditions and the leading cause of disability. Chronic pain disproportionately affects certain populations including women, low-income individuals, and older adults. This article focuses primarily on new molecular entities in development targeting various chronic pain receptors and new delivery technologies.
Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.
Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine’s action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.
Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine’s analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine’s ability to modulate the affective-motivational dimension of pain.
We have compared the analgesic efficacy of the racemic mixture and the stereoisomer (S+) of the NMDA antagonist ketamine.
In a double-blind, three-way crossover, placebo-controlled study, we assessed the following: pain evoked by small/large area
pressure stimuli, pain detection threshold and pain ratings to small/large area of heat stimuli, pain detection threshold
and pain rating to heat stimuli of brief/long duration, summation pain threshold and pain ratings to repeated heat/electrical
stimuli, side effects and reaction time. Plasma concentrations of 350 ng ml-1 for ketamine (racemic) and 180 ng ml-1 for ketamine
(S+) were tried. We found that ketamine (racemic) prolonged the reaction time more than ketamine (S+). Both drugs affected
pain caused by repeated stimuli or stimuli of long duration equally or more than a single stimulus of short duration. They
also affected pain evoked from large areas equally or more than pain evoked from small areas. The (S+)-isomer was approximately
twice as potent as the racemic mixture of ketamine in inhibiting central summation.
Hyperexcitability of N-methyl-D-aspartate (NMDA) receptors may play a role in the persistence of phantom pain. Dextromethorphan (DM) blocks NMDA receptors.
Eight cancer and two noncancer amputees with established, disabling phantom pain received oral DM 60 or 90 mg twice daily (BID) in a three-period double-blind crossover placebo-controlled trial. This followed an open-phase trial in which either dose was given three times daily if pain relief during the double-blind phase was <50% of pretreatment intensity. Patients then underwent a 3-month phase of treatment with the best regimen and a subsequent 1-month posttreatment follow-up.
All patients reported a >50% decrease in pain intensity, better mood, and lower sedation in each treatment phase. Four individuals reported this level of pain relief with the 60-mg and one with the 90-mg BID regimen during the double-blind phase, whereas two amputees benefited from the 60-mg and three from the 90-mg thrice-daily regimen in the open-phase trial. One reported exacerbation of pain with the 90-mg BID regimen, and three reported pain rebound at the 1-month posttreatment follow-up phase. Three patients stopped all previous analgesic use during the study.
Persistent phantom pain probably involves NMDA receptor hyperexcitability because DM 120 to 270 mg/day mitigated the pain satisfactorily.
Phantom limb pain (PLP) associated neuroplastic changes are partly mediated by excitatory amino acids at NMDA receptor sites. This study was undertaken to deduce if NMDA-receptor antagonists may be effective in patients with chronic PLP. Therefore a four week double-blinded, randomized placebo-controlled trial was performed to evaluate the efficacy of 30 mg memantine/day, an orally administrable NMDA receptor antagonist.Thirty-six patients, 18 per group, with a history of at least 12 months PLP and an average pain of at least 4 on the 11-point numeric rating scale (NRS) were enrolled. The patients completed a standardized questionnaire before the trial. PLP intensity and the level of eight complaints were assessed during the trial. Number needed to treat (NNT) was calculated based on the average PLP during the 3rd week (steady state). In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 (+/-2.1) to 3,8 (+/-2,3), placebo from 5.1 (+/-2.0) to 3.2 (+/-1,46) NRS) without a re-rising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10 patients reported more than 50% relief), 40% in the placebo group (6>50%): NNT were 4.5 (KI: 2.1-10.6). Analysis of covariance demonstrated a significant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long-term pain relief under memantine until now (16 months). The total number of slight adverse events were comparable in both groups, but the overall number of severe events was higher in the memantine group (P<0.05). This trial failed to demonstrate a significant clinical benefit of the NMDA-receptor antagonist memantine in chronic PLP. The administration of a higher dosage is probably not tolerable.
We hypothesized that perioperative ketamine administration would modify acute central sensitization following amputation and hence reduce the incidence and severity of persistent post-amputation pain (both phantom limb and stump pain). In a randomized, controlled trial, 45 patients undergoing above- or below-knee amputation received ketamine 0.5 mg.kg –1 or placebo as a pre-induction bolus followed by an intravenous infusion of ketamine 0.15 mg.kg –1 .h –1 or normal saline for 72 hours postoperatively. Both groups received standardized general anaesthesia followed by patient-controlled intravenous morphine. The surface area of allodynia over the stump was mapped at days 3 and 6. Postamputation pain was assessed at days 3 and 6 and at 6 months postoperatively.
We found no significant difference between groups in the surface area of stump allodynia or in morphine consumption. There was an unexplained, but significant, increase in the incidence of stump pain in the ketamine group at day 3. At six-month review, the incidence of phantom pain was 47% in the ketamine group and 71% in the control group. This did not reach statistical significance (P=0.28) as the power of the study was based on the search for a large treatment effect. The incidence of stump pain at six months was 47% in the ketamine group and 35% in the control group (P=0.72). There were no significant between-group differences in pain severity throughout the study period.
Ketamine at the dose administered did not significantly reduce acute central sensitization or the incidence and severity of post-amputation pain.
Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor channel blocker known to inhibit "wind-up" and hence central hyperexcitability of dorsal horn neurons. We sought to assess the effect of ketamine on single and repeated nociceptive stimuli. A placebo-controlled, human (12 volunteers) experimental study was conducted in which several psychophysical (pain detection and tolerance thresholds, magnitude ratings) and electrophysiologic (withdrawal reflex) techniques were used 1) to investigate whether a ketamine (0.5 mg/kg) bolus followed by a 20-min infusion (9 micro gram centered dot kg-1 centered dot min-1) inhibits central temporal summation to repeated nociceptive electrical stimuli, and 2) to assess quantitatively the hypoalgesic potency using several experimental nociceptive stimuli (argon laser, pressure, electrical). Facilitation of the withdrawal reflex to and pain rating of repeated electrical stimuli (five pulses at 2 Hz) were inhibited by ketamine. Reflex and pain rating to a single stimulus did not change. The pressure pain detection and tolerance thresholds were increased significantly by ketamine, whereas the laser heat pain and tolerance thresholds remained stable compared with placebo. The stimulus response function showed that ketamine reduced the responses to the highest electrical stimulus intensities (1.4, 1.6, and 1.8 times the reflex threshold). We conclude that ketamine inhibits central temporal summation in humans and has a marked hypoalgesic effect on high intensity nociceptive stimuli. (Anesth Analg 1995;81:63-8)
Animal experiments have shown that the nociceptive reflex can be used as an indicator of central temporal integration in the nociceptive system. The aim of the present study on humans was to investigate whether the nociceptive reflex, evoked by repetitive strong electrical sural nerve stimuli, increased when summation was reported by the volunteers. The reflexes were recorded from the biceps femoris and rectus femoris muscles in eight volunteers following a series of stimulations at 0.1, 1, 2, and 3 Hz. Each series consisted of five consecutive stimuli. Using 0.1- and 1-Hz stimulation, the reflex was not facilitated in the course of the five consecutive stimuli. Following 2- and 3-Hz stimulation, the reflex size (root mean square amplitude) increased significantly during the course of the fifth stimulus. This reflex facilitation was followed by a significant increase (summation) in the pain magnitude when compared with 1- and 0.1-Hz stimulation. Furthermore, the threshold for psychophysical summation could be determined. This threshold (stimulus intensity) decreased when the stimulus frequency (1–5 Hz) of the five consecutive stimuli was increased. The nociceptive reflex and the psychophysical summation threshold might be used to clarify and quantify aspects of temporal summation within the human nociceptive system.
Salmon calcitonin (s-CT) has been shown to be a valuable analgesic in phantom limb pain (PLP) in several case reports. To evaluate these findings a double-blind crossover comparison of s-CT treatment versus placebo was initiated.Twenty-one out of 161 patients who had undergone major amputations and developed severe PLP 0–7 days after surgery were included in the study. For each patient a matched pair of infusions was prepared containing either 200 IU of s-CT or placebo. Group I (n = 11) was first given s-CT and group II (n = 10) placebo. When PLP reached a level of more than 3 on a numeric analogue scale (NAS) the first infusion was administered. The second infusion (crossover) or more infusions were given when the pain level again exceeded more than 3 on NAS.Using s-CT infusion, PLP was eased from a median of 7 to 4 on NAS in both groups (P < 0.001), regardless of whether s-CT or placebo was given first. Placebo, however, did not change pain scores (median 7 on NAS, P > 0.1). In the s-CT group, but not in the placebo group, 4 individuals remained pain free without a second infusion. Any further treatment was performed with s-CT. One week after the first PLP treatment 19 patients (90%) had pain relief of more than 50%, 16 (76%) were completely pain free, and 15 (71%) never experienced PLP again. One year later 8 out of the 13 surviving patients (62%) still had more than 75% PLP relief. After 2 years PLP exceeded 3 on NAS in 5 individuals (42%), and the remaining 12 patients presented the same PLP as after 1 year.In conclusion, s-CT is a valuable treatment for PLP in the early postoperative period.
Chronic pain, lymphoedema, post-irradiation neuropathy and other symptoms are reported in as many as 75% of women following breast cancer treatment. This study examined pain and sensory abnormalities in women following breast cancer surgery. Sensory tests were carried out on operated and contralateral sides in 15 women with spontaneous pain and sensory abnormalities and 11 pain-free women. Testing included the VAS score of spontaneous pain, detection and pain threshold to thermal and mechanical stimuli, temporal summation to repetitive heat and pinprick stimuli, and assessment of skin blood flow during repetitive brush and pinprick stimulation. Sensory threshold to pinprick and thermal stimuli was significantly higher on the operated side in both groups while pressure pain threshold was significantly lower in pain patients on the operated side compared to the contralateral side. No side to side difference was seen in pressure pain threshold in the pain-free group. Evoked pain intensity to repetitive stimuli at 0.2 and 2.0 Hz was significantly higher on the operated side in pain patients compared to the control area while no such difference was seen in pain-free patients. Cutaneous blood flow measured by laser Doppler (flux) was significantly higher when the skin was tapped at 2.0 Hz on the operated side compared to contralaterally in pain patients, while no side to side difference was seen in pain-free patients. Pinprick-evoked pain was correlated to spontaneous pain but not to flux. Spontaneous pain was not correlated to flux. Sensitization seems to be a feature in breast cancer-operated women with pain, but not in pain-free women.
Salmon calcitonin (s-CT) has been shown to be a valuable analgesic in phantom limb pain (PLP) in several case reports. To evaluate these findings a double-blind crossover comparison of s-CT treatment versus placebo was initiated. Twenty-one out of 161 patients who had undergone major amputations and developed severe PLP 0-7 days after surgery were included in the study. For each patient a matched pair of infusions was prepared containing either 200 IU of s-CT or placebo. Group I (n = 11) was first given s-CT and group II (n = 10) placebo. When PLP reached a level of more than 3 on a numeric analogue scale (NAS) the first infusion was administered. The second infusion (crossover) or more infusions were given when the pain level again exceeded more than 3 on NAS. Using s-CT infusion, PLP was eased from a median of 7 to 4 on NAS in both groups (P less than 0.001), regardless of whether s-CT or placebo was given first. Placebo, however, did not change pain scores (median 7 on NAS, P greater than 0.1). In the s-CT group, but not in the placebo group, 4 individuals remained pain free without a second infusion. Any further treatment was performed with s-CT. One week after the first PLP treatment 19 patients (90%) had pain relief of more than 50%, 16 (76%) were completely pain free, and 15 (71%) never experienced PLP again. One year later 8 out of the 13 surviving patients (62%) still had more than 75% PLP relief. After 2 years PLP exceeded 3 on NAS in 5 individuals (42%), and the remaining 12 patients presented the same PLP as after 1 year. In conclusion, s-CT is a valuable treatment for PLP in the early postoperative period.
Characteristics of first and second pain (human subjects) and flexion reflexes (spinal cats) were studied to assess their consistency with dorsal horn cell responses to cutaneous A and C fiber stimulation. For both experiments, two percutaneous electrical shock intensities were used to activate only A fibers and both A and C fibers. Selective block of ulnar nerve impulses necessary for first (pricking) pain was achieved by pressure to the ventral forearm. During blockade, sensation thresholds to shock and graded von Fry hairs increased progressively. After about 40 min, touch, first pain, and pinprick were no longer perceived, but long-latency (> 1 sec) burning sensations due to intense shocks and strong pinch persisted. Differences in reaction time to first and second pain indicated that second pain was related to impulses conducting between 0.8 and 1.6 m/sec (mean = 1.3 m/sec). Sensations of second pain increased with each successive shock if stimulus frequencies were greater than 0.3/sec. These progressive increases occurred both before and after blockade of first pain but not with shock intensities sufficient only to produce first pain. Second pain could be selectively suppressed by mildly painful clamping of adjacent or contralateral digits. A similar analysis applied to flexion reflexes showed that late (or second) flexion reflexes increased progressively when C fibers were activated and when shock frequency exceeded 0.3/sec. The stimulus intensities and frequencies of shocks producing progressively more intense second pain and late flexion reflexes are consistent with previously observed increases in dorsal horn responses to iterative C fiber stimulation.
Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor channel blocker known to inhibit "wind-up" and hence central hyperexcitability of dorsal horn neurons. We sought to assess the effect of ketamine on single and repeated nociceptive stimuli. A placebo-controlled, human (12 volunteers) experimental study was conducted in which several psychophysical (pain detection and tolerance thresholds, magnitude ratings) and electrophysiologic (withdrawal reflex) techniques were used 1) to investigate whether a ketamine (0.5 mg/kg) bolus followed by a 20-min infusion (9 micrograms.kg-1.min-1) inhibits central temporal summation to repeated nociceptive electrical stimuli, and 2) to assess quantitatively the hypoalgesic potency using several experimental nociceptive stimuli (argon laser, pressure, electrical). Facilitation of the withdrawal reflex to and pain rating of repeated electrical stimuli (five pulses at 2 Hz) were inhibited by ketamine. Reflex and pain rating to a single stimulus did not change. The pressure pain detection and tolerance thresholds were increased significantly by ketamine, whereas the laser heat pain and tolerance thresholds remained stable compared with placebo. The stimulus response function showed that ketamine reduced the responses to the highest electrical stimulus intensities (1.4, 1.6, and 1.8 times the reflex threshold). We conclude that ketamine inhibits central temporal summation in humans and has a marked hypoalgesic effect on high intensity nociceptive stimuli.
Hyperactivity of N-methyl D-aspartate (NMDA) receptors may be one of the factors in the maintenance of persistent stump and phantom limb pain. Ketamine (bolus at 0.1 mg/kg/5 min followed by an infusion of 7 micrograms/kg/min) was administered intravenously to 11 patients with established stump and phantom limb pain in a double-blind saline-controlled study. All 11 patients responded with a decrease in the rating of stump and phantom limb pain assessed by visual analogue scale (VAS) and McGill Pain Questionnaire (MPQ). Ketamine increased pressure-pain thresholds significantly. Wind-up like pain (pain evoked by repeatedly tapping the dysaesthetic skin area) was reduced significantly by ketamine. In contrast, no effect was seen on pain evoked by repeated thermal stimuli. Side effects were observed in nine patients. The results support the notion that stump and phantom pain are generated by activity in afferent fibres activated by mechanical but not by thermal stimuli and that the NMDA receptor is involved in the maintenance of postamputation pain states. NMDA receptor antagonists may have a potential in the treatment of stump and phantom limb pain.
Effects of morphine and ketamine (NMDA receptor antagonist) on temporally summated pain ('wind-up-like pain') and spatial aspects of secondary hyperalgesia were investigated in 12 healthy volunteers. Hyperalgesia was produced by a local 1 degree burn injury covering 12.5 cm2 on the medial surface of the calf. Primary hyperalgesia was determined by measuring heat pain detection threshold (HPDT) within the site of injury. Spatial aspects of secondary hyperalgesia present outside the site of injury were quantitated by determination of the areas in which a mechanical punctate (von Frey hair, 50.6 mN), or brush stimuli elicited pain sensation. Temporal aspects of secondary hyperalgesia were determined by repetitively pricking the skin with a standard von Frey hair (834 mN) inducing a 'wind-up-like pain'. Morphine 0.15 mg/kg, ketamine 0.15 mg/kg or placebo (NaCl 0.9%) were administrated i.v. on 3 separate days 50 min after the burn injury in a double-blind, placebo controlled, randomised and cross-over design. In all subjects HPDT was significantly reduced within the injured area compared to the pre-injury threshold (primary hyperalgesia). All subjects developed areas of allodynia and hyperalgesia to punctate stimuli and brush stimuli outside the injured area (secondary hyperalgesia). HPDT was not reduced in the area of secondary hyperalgesia. In 95% of the measurements we found a sudden appearance of pain to repeated pricking with a von Frey hair (834 mN) in the area of secondary hyperalgesia ('wind-up-like pain'). Ketamine significantly reduced the area of secondary hyperalgesia both for punctate and brush stimuli in the first measurement 15 min after injection and eight of the 11 subjects reported that the 'wind-up-like pain' disappeared. On the measurements 45 and 75 min after ketamine injection, secondary hyperalgesia and 'wind-up-like pain' reappeared. Morphine did not significantly change the size of the area of secondary hyperalgesia and did not affect 'wind-up-like pain'. Ketamine or morphine did not change thermal detection thresholds. We conclude that spatial and temporal mechanisms, underlying secondary hyperalgesia, are mediated by glutamatergic transmission via NMDA receptors.
The significance of preamputation pain for the development of postamputation stump and phantom pain has been discussed over the years and is still a matter of dispute. It has been argued that preamputation pain increases the risk of phantom pain and that phantom pain is a revivification of pain experienced before the amputation. The purpose of this prospective study was to clarify the relation between preamputation pain and phantom pain. Fifty-six patients scheduled for amputation of a lower limb were interviewed the day before the amputation about preamputation pain and about stump and phantom pain 1 week, 3 and 6 months after the amputation. Pain was quantitated and described using a visual analogue scale (VAS), 10 different word descriptors, the McGill Pain Questionnaire (MPQ) and the patients' own words. If phantom pain was present patients were asked if the pain was similar to any pain experienced before the amputation. At each postoperative interview patients were asked to recall preamputation pain intensity. Location of pain and analgesic requirements were registered. Preamputation pain significantly increased the incidence of stump pain (P = 0.04) and phantom pain (P = 0.04) after 1 week and the incidence of phantom pain after 3 months (P = 0.03). About 42% of the patients reported that their phantom pain resembled the pain they had experienced at the time of the amputation. However, there was no relation between the patients' own opinion about similarity between preamputation pain and phantom pain and the actual similarity found when comparing pre- and postoperative recordings of pain. Patients significantly overestimated preamputation pain intensity after 6 months.
Epidural analgesia before limb amputation is commonly used to reduce postamputation pain. But there have been no controlled studies with large numbers of patients to prove such a pre-emptive effect. We investigated whether postamputation stump and phantom pain in the first year is reduced by preoperative epidural blockade with bupivacaine and morphine.
In a randomised, double-blind trial, 60 patients scheduled for lower-limb amputation were randomly assigned epidural bupivacaine (0.25% 4-7 mL/h) and morphine (0.16-0.28 mg/h) for 18 h before and during the operation (29 patients; blockade group) or epidural saline (4-7 mL/h) and oral or intramuscular morphine (31 patients; control group). All patients had general anaesthesia for the amputation and were asked about stump and phantom pain after 1 week and then after 3, 6, and 12 months by two independent examiners. Study endpoints were rate of stump and phantom pain, intensity of stump and phantom pain, and consumption of opioids.
Two patients in each group were withdrawn before amputation. The groups were well matched in baseline characteristics. Median duration of preoperative saline treatment was 18.5 h (IQR 17-20). Median duration of preoperative epidural blockade in the blockade group was 18 h (15-20.3). The combined median duration of postoperative epidural pain treatment in both groups was 166 h (89.3-308.3). After 1 week, 14 (52%) patients in the blockade group and 15 (56%) in the control group had phantom pain (95% CI - 30.6 to 22.7, p = 0.9). The figures for blockade versus control group were: 14 (82%) vs ten (50%; 4.0 to 60.8, p = 0.09) at 3 months; 13 (81%) vs 11 (55%; -2.7 to 55.3, p = 0.2) at 6 months; and nine (75%) vs 11 (69%; -27.0 to 39.6, p = 1.0) at 12 months. Intensity of stump and phantom pain and consumption of opioids were similar in both groups at all four postoperative interviews.
Perioperative epidural blockade started a median of 18 h (15-20.3) before the amputation and continued into the postoperative period does not prevent phantom or stump pain.
Anecdotal reports suggest that the general anaesthetic drug ketamine, taken orally in low doses, can give rise to some extra analgesia in patients with refractory neuropathic pain. This study was designed to determine the proportion of patients with chronic neuropathic pain responding to oral ketamine, and then to separate the true treatment effect from non-specific effects by means of an n of 1 randomised controlled trial. Twenty-one patients gave informed consent and completed daily pain diaries and continued on their usual treatments (drug and non-drug) for the duration of the study. After a 'baseline' week, oral ketamine was taken once a day for 1 week. The dose of 20 mg was increased each day until an analgesic effect was noticed or adverse effects occurred, or until a maximum of 100 mg was reached. Those patients responding to oral ketamine were then entered into the n of 1 randomised trial which consisted of three treatment/placebo week pairs. Twelve patients did not progress to the n of 1 trial because of no benefit and/or intolerable adverse effects (dizziness, drowsiness etc.). Nine patients completed the n of 1 trial; there was no difference between the ketamine and placebo weeks in six patients; one patient demonstrated effective analgesia with ketamine, but it was of short duration and marred by unpleasant adverse effects; two patients showed some evidence of a beneficial response to ketamine, and continued with the oral ketamine after the trial. We conclude that oral ketamine only gave rise to an extra analgesic response in three out of 21 patients with chronic neuropathic pain (14%). Adverse effects limited the use of the drug in almost half of the patients. The n of 1 trial was useful in demonstrating no true therapeutic effect for the ketamine in two thirds of the patients progressing to that part of the trial.
The whiplash syndrome has immense socio-economic impact. Despite extensive studies over the past years, the mechanisms involved in maintaining the pain in chronic whiplash patients are poorly understood. The aim of the present experimental study was to examine the muscular sensibility in areas within and outside the region involved in the whiplash trauma. Eleven chronic whiplash patients and 11 sex and age matched control subjects were included in the study. Before the experiment, the whiplash patients had pain in the neck and shoulder region with radiating pain to the arm. Five patients reported pain that was more widespread. The somatosensory sensibility in the areas over the infraspinatus, brachioradial, and anterior tibial muscles was assessed by pressure stimulation, pin-prick stimulation, and cotton swap stimulation. Infusion of hypertonic saline (5.85%, 0.5 ml) into the infraspinatus and anterior tibial muscles was performed to assess the muscular sensibility and referred pain pattern. The saline-induced muscle pain intensity was assessed on a continuous visual analogue scale (VAS). The distribution of pain was drawn on an anatomical map. The pressure pain thresholds were significantly lower in patients (P<0. 01) compared with controls: infraspinatus (mean 152.2 vs. 172.7 kPa), brachioradial (mean 70.0 vs. 363.8 kPa), and anterior tibial muscle (mean 172.7 vs. 497.8 kPa). The skin sensibility to pin-prick stimulation and cotton swap stimulation was not different between patients and controls. Infusion of hypertonic saline caused significantly higher VAS scores with longer duration in patients compared to control subjects (P<0.01). The area under the VAS-time curve was significantly (P<0.01) increased in patients compared to control subjects after injection into the infraspinatus muscle (mean 4138.1 vs. 780.0 cm s) and anterior tibial muscle (mean 4370.8 vs. 978.7 cm s). The saline infusion caused local pain defined as pain located around the injection site and referred pain areas not included in the local pain area. The area of local and referred pain were significantly larger in patients compared to control subjects (P<0.01). In the control group, the referred pain areas to infusion of hypertonic saline into the anterior tibial muscle were found at the dorsal aspect of the ankle. In contrast, the areas of referred pain were quite widespread in the patient group with both distal and proximal referred pain areas. In the present study, muscular hyperalgesia and large referred pain areas were found in patients with chronic whiplash syndrome compared to control subjects both within and outside the traumatised area. The findings suggest a generalised central hyperexcitability in patients suffering from chronic whiplash syndrome. This indicates that the pain might be considered as a neurogenic type of pain, and new pharmacological treatments should be investigated accordingly.
Unlabelled:
Animal studies have suggested that the temporal summation of nociceptive inputs might play a significant role in the development of central sensitization (i.e., hyperexcitability of central nociceptive neurons) and hyperalgesia via the activation of N-methyl-D-aspartate receptors. To further analyze these processes in humans, we evaluated the effects of small systemic doses of ketamine on the temporal summation (i.e., wind-up) of both the nociceptive flexion (R(III)) reflex and sensations of pain in six healthy volunteers. The R(III) reflex was recorded from the biceps femoris and was elicited by electrical stimulation of the sural nerve. First, the recruitment (stimulus/response) curve for the reflex was built using stimuli up to the pain tolerance threshold (applied once every 6 s). A series of 15 stimuli was then applied once a second at an intensity of 1.2 times the reflex threshold. These procedures were performed both before and after the randomized IV injection of either 0.15 mg/kg ketamine or a placebo. The R(III) reflex threshold and its recruitment curve were not significantly altered after the injection of ketamine or placebo. By contrast, the significant increases (i.e., wind-up) in both the reflex responses and the sensations of pain observed during the higher frequency stimulation were significantly reduced after the administration of ketamine, but not placebo. This method might be useful for quantifying and analyzing the wind-up phenomenon and, thus, for studying the neurophysiological and pharmacological mechanisms underlying hyperalgesia in humans.
Implications:
The wind-up phenomenon (i.e., the progressive increase of the responses induced by repetitive nociceptive stimuli) was characterized in humans by using electrophysiological recordings of the nociceptive flexion reflex. We showed that, as in animals, this phenomenon, which might represent an elementary form of the central sensitization involved in various painful syndromes, depends on the activation of N-methyl-D-aspartate receptors, because it was selectively reduced after the administration of ketamine.
Phantom pain in subjects with an amputated limb is a well-known problem. However, estimates of the prevalence of phantom pain differ considerably in the literature. Various factors associated with phantom pain have been described including pain before the amputation, gender, dominance, and time elapsed since the amputation. The purposes of this study were to determine prevalence and factors associated with phantom pain and phantom sensations in upper limb amputees in The Netherlands. Additionally, the relationship between phantom pain, phantom sensations and prosthesis use in upper limb amputees was investigated. One hundred twenty-four upper limb amputees participated in this study. Subjects were asked to fill out a self-developed questionnaire scoring the following items: date, side, level, and reason of amputation, duration of experienced pain before amputation, frequencies with which phantom sensations, phantom pain, and stump pain are experienced, amount of trouble and suffering experienced, respectively, related to these sensations, type of phantom sensations, medical treatment received for phantom pain and/or stump pain, and the effects of the treatment, self medication, and prosthesis use. The response rate was 80%. The prevalence of phantom pain was 51%, of phantom sensations 76% and of stump pain 49%; 48% of the subjects experienced phantom pain a few times per day or more; 64% experienced moderate to very much suffering from the phantom pain. A significant association was found between phantom pain and phantom sensations (relative risk 11.3) and between phantom pain and stump pain (relative risk 1.9). No other factors associated with phantom pain or phantom sensations could be determined. Only four patients received medical treatment for their phantom pain. Phantom pain is a common problem in upper limb amputees that causes considerable suffering for the subjects involved. Only a minority of subjects are treated for phantom pain. Further research is needed to determine factors associated with phantom pain.
Unlabelled:
Evidence has accumulated that the N:-methyl-D-aspartate receptor system plays a role in continuous and particularly, in stimulus-evoked pain after nerve injury. We examined, in a randomized, double-blinded, cross-over fashion, the analgesic effect of memantine (a N:-methyl-D-aspartate receptor antagonist) in a group of patients with chronic pain after surgery. We randomized 19 patients to receive either memantine or placebo in the first 5-wk treatment period. A washout period of 4 wks was followed by another 5-wk treatment period with the opposite drug. The dosage of drug was increased from 5 to 20 mg/d. Pain was recorded daily, with the use of a 0-10 numeric rating scale. Before and at the end of each treatment period, pain and sensitivity were also assessed by using the McGill Pain Questionnaire, allodynia to touch, brush and cold, wind-up-like pain, and thresholds to mechanical stimuli (pressure and von Frey hair). A total of 15 patients (12 amputees and three patients with other nerve injuries) completed the study. There was no difference between memantine and placebo on any of the outcome measures. We conclude that memantine at a dosage of 20 mg/d does not reduce spontaneous or evoked pain in patients with nerve injury pain.
Implications:
In a randomized, double-blinded and cross-over study, the analgesic effect of memantine (a drug which reduces the excitability of sensitized neurons in the dorsal horn) was examined in 19 patients with chronic pain after nerve injury.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and has been proven effective in alleviating secondary hyperalgesia in human subjects when injected intravenously. After oral ingestion, ketamine is metabolized into norketamine, which in vitro possesses NMDA receptor antagonistic effect. The aim of this study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia evoked by standardized tissue injury.
Twenty-four male volunteers were included in the study. Each volunteer received the following treatment regimen, in randomized, double-blind, 3-way cross-over fashion: (A) placebo; (B) ketamine, 0.5 mg/kg; and (C) ketamine, 1.0 mg/kg. Standardized tissue injury was induced after study medication by heating the right calf with a rectangular thermode. The temperature was 47 degrees C, and heating time was 7 minutes. The following parameters were investigated: Pain during induction of the burn injury; heat-pain detection thresholds in the injured area and a corresponding noninjured area; secondary hyperalgesia surrounding the injured area on the calf; secondary hyperalgesia induced by heating an area on the thigh with 45 degrees C in 3 minutes; pressure-pain detection thresholds measured on the middle phalanx of the 4th left finger; pain during a 60-second thermal stimulation of 46 degrees C on undamaged skin on the left thigh; and side effects.
Some degree of sedation was observed after oral administration of ketamine. No effects on any of the other investigated parameters were observed.
Oral ketamine 0.5 or 1.0 mg/kg has no effect on secondary hyperalgesia or thermal or mechanical pain thresholds in human volunteers.
This review documents a high incidence of chronic pain after five common surgeries. The authors review the data regarding factors that predict the occurence of chronic pain in these populations.
The efficacy of oral retarded morphine sulphate (MST) was tested against placebo in a double-blind crossover design in 12 patients with phantom limb pain after unilateral leg or arm amputation. Two counterbalanced treatment phases of 4 weeks each were initiated with an intravenous test infusion of MST or Placebo. The titration phase was 2 weeks. The dose of MST was titrated to at least 70 mg/day and at highest 300 mg/day. Pain intensity was assessed hourly on visual analog scales during a 4-week treatment-free phase, both treatment phases and at two follow-ups (6 and 12 months). Reorganization of somatosensory cortex, electric perception and pain thresholds as well as selective attention were measured pre- and post-treatment. A significant pain reduction was found during MST but not during placebo. A clinically relevant response to MST (pain reduction of more than 50%) was evident in 42%, a partial response (pain reduction of 25-50%) in 8% of the patients. Neuromagnetic source imaging of three patients showed initial evidence for reduced cortical reorganization under MST concurrent with the reduction in pain intensity. Perception and pain thresholds were not significantly altered whereas attention was significantly lower under MST. Thus, opioids show efficacy in the treatment of phantom limb pain and may potentially influence also cortical reorganization. These data need to be replicated in larger patient samples.
Hypertonic saline effectively excites muscle nociceptors. Muscle hyperalgesia was assessed in osteoarthritis (OA) by intramuscular infusion of 0.5 ml hypertonic saline (6%) into the tibialis anterior muscle in humans. Patients (n=14) with OA in the lower extremities were compared with an equal number of age- and sex-matched healthy controls. Ten of the 14 OA patients had pain in the knee joint as the most common presenting complaint. Visual analogue scale (VAS) pain intensity and assessment of pain areas were recorded before infusion and immediately, 2, 5, 10 and 20 min after infusion, and then every 10 min, until the pain vanished. The mean pain offset time in OA patients (11.3+/-7.9 min) was larger as compared with the control subjects (6.04+/-2.1 min) (P=0.025). OA patients had increased pain intensity VAS after the infusion in the right leg compared with controls (P<0.05). Referred and radiating pain areas at 2 min post-infusion increased in OA patients and not in controls as compared with the local pain areas (P<0.05). It is concluded that muscle hyperalgesia and extended pain areas might be due to central sensitization caused by painful osteoarthritis.
The mechanisms underlying chronic pain after whiplash injury are usually unclear. Injuries may cause sensitization of spinal cord neurons in animals (central hypersensitivity), which results in increased responsiveness to peripheral stimuli. In humans, the responsiveness of the central nervous system to peripheral stimulation may be explored by applying sensory tests to healthy tissues. The hypotheses of this study were: (1) chronic whiplash pain is associated with central hypersensitivity; (2) central hypersensitivity is maintained by nociception arising from the painful or tender muscles in the neck.
Comparison of patients with healthy controls.
Pain clinic and laboratory for pain research, university hospital.
Fourteen patients with chronic neck pain after whiplash injury (car accident) and 14 healthy volunteers.
Pain thresholds to: single electrical stimulus (intramuscular), repeated electrical stimulation (intramuscular and transcutaneous), and heat (transcutaneous). Each threshold was measured at neck and lower limb, before and after local anesthesia of the painful and tender muscles of the neck.
The whiplash group had significantly lower pain thresholds for all tests. except heat, at both neck and lower limb. Local anesthesia of the painful and tender points affected neither intensity of neck pain nor pain thresholds.
The authors found a hypersensitivity to peripheral stimulation in whiplash patients. Hypersensitivity was observed after cutaneous and muscular stimulation, at both neck and lower limb. Because hypersensitivity was observed in healthy tissues, it resulted from alterations in the central processing of sensory stimuli (central hypersensitivity). Central hypersensitivity was not dependent on a nociceptive input arising from the painful and tender muscles.
Phantom and stump pains, common sequelae of limb amputations, are significant impediments to rehabilitation of amputees. The pathophysiology and optimal treatment of postamputation pain states are unclear. While stump pain may result from neuromas in the stump, phantom pain is thought to be related to cortical reorganization. The authors hypothesized that morphine and lidocaine may have differential effectiveness on stump and phantom pains.
The authors conducted a randomized double-blind, active-placebo-controlled, crossover trial to compare the analgesic effects of intravenous morphine and lidocaine on postamputation stump and phantom pains. An intravenous bolus followed by an intravenous infusion of morphine (0.05 mg/kg bolus + 0.2 mg/kg infusion over 40 min), lidocaine (1 mg/kg bolus + 4 mg/kg infusion) and the active placebo, diphenhydramine (10 mg bolus + 40 mg infusion), were performed on three consecutive days. Phantom and stump pain ratings and sedation scores were recorded at 5-min intervals using a 0-100 visual analog scale. Pain measures were initiated 30 min before drug infusion and continued until 30 min after the end of infusion. Subjects' self-reported pain relief and satisfaction were assessed at the end of each infusion.
Thirty-one of 32 subjects enrolled completed the study. Eleven subjects had both stump and phantom pains, 11 and 9 subjects had stump and phantom pain alone, respectively. Baseline pain scores were similar in the three drug groups. Compared with placebo, morphine reduced both stump and phantom pains significantly (P < 0.01). In contrast, lidocaine decreased stump (P < 0.01), but not phantom pain. The changes in sedation scores for morphine and lidocaine were not significantly different from placebo. Compared with placebo, self-reported stump pain relief was significantly greater for lidocaine (P < 0.05) and morphine (P < 0.01), while phantom pain relief was greater only for morphine (P < 0.01). Satisfaction scores were significantly higher for lidocaine (mean +/- SD: 39.3 +/- 37.8, P < 0.01) and morphine (45.9 +/- 35.5, P < 0.01) when compared with placebo (9.6 +/- 21.0).
Stump pain was diminished both by morphine and lidocaine, while phantom pain was diminished only by morphine, suggesting that the mechanisms and pharmacological sensitivity of stump and phantom pains are different.
The analgesic activity of calcitonin is well established, both through clinical observation and specific experimental investigation. The mechanism involved, however, is still unclear, and the hypotheses that have been proposed range from a simple peripheral antiinflammatory action to a direct action on specific receptors in the central nervous system. The various hypotheses are briefly reviewed and some of the supporting evidence is presented. The conclusion is that the principal mechanism of calcitonin's analgesic effect is probably a direct central action, but that this is further supported by peripheral mechanisms that may also improve bone status locally.
The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers.
The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.
Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively.
Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.
Severe phantom limb pain after surgical amputation affects 50% to 67% of patients and is difficult to treat. Gabapentin is effective in several syndromes of neuropathic pain. Therefore, we evaluated its analgesic efficacy in phantom limb pain.
Patients attending a multidisciplinary pain clinic with phantom limb pain were enrolled into this randomized, double-blind, placebo-controlled, cross-over study. Other anticonvulsant therapy was discontinued. Each treatment was 6 weeks separated by a 1-week washout period. Codeine/paracetamol was allowed as rescue analgesia. The daily dose of gabapentin was titrated in increments of 300 mg to 2400 mg or the maximum tolerated dose. Patients were assessed at weekly intervals. The primary outcome measure was visual analog scale (VAS) pain intensity difference (PID) compared with baseline at the end of each treatment. Secondary measures were indices of sleep interference, depression (Hospital Anxiety and Depression [HAD] scale), and activities of daily living (Bartel Index).
Nineteen eligible patients (mean age, 56 years; range, 24 to 68 years; 16 men) were randomized, of whom 14 completed both arms of the study. Both placebo and gabapentin treatments resulted in reduced VAS scores compared with baseline. PID was significantly greater than placebo for gabapentin therapy at the end of the treatment (3.2 +/- 2.1 v 1.6 +/- 0.7, P =.03). There were no significant differences between placebo and gabapentin therapy in terms of the number of tablets of rescue medication required, sleep interference, HAD scale, or Bartel Index. The medication was well tolerated with few reports of adverse effects.
After 6 weeks, gabapentin monotherapy was better than placebo in relieving postamputation phantom limb pain. There were no significant differences in mood, sleep interference, or activities of daily living, but a type II error cannot be excluded for these variables.
Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.
Muscle pain is a major clinical problem but the underlying mechanisms and its pharmacological modulation need further investigation. This study on 15 volunteers evaluates if two experimental muscle pain models are sensitive to micro -receptor agonists and to an N-methyl-D-aspartate (NMDA)-receptor antagonist.
In the left tibialis anterior, intramuscular electrical (IMES) pain thresholds were determined for single (SPTmuscle) and five (RPTmuscle) repeated stimuli. Also pain to suprathreshold stimulation at 150% of RPTmuscle, 10 s, was assessed on a visual analog scale (VAS) as AUCimes (area under the VAS curve). In the right TA muscle, pain intensity on infusion of 0.5 ml of hypertonic saline, 5% (AUCsaline) and pain distribution indicated as local and referred were evaluated. Pain variables were assessed before, during and after intravenous infusions of morphine (10 microg x kg-1 min-1, 10 min), alfentanil (target-controlled infusion, plasma concentration; 60 ng ml-1, 60 min) and ketamine (10 microg x kg-1 min-1, 60 min). All data were normalized to baseline pain values (before drug infusions were initiated) and compared with placebo (midazolam, 2 microg x kg-1 min-1, 10 min).
SPTmuscle increased (log mean values +/- SD, mA) with morphine (0.11 +/- 0.17, P < 0.05), alfentanil (0.28 +/- 0.24, P < 0.001) and ketamine (0.19 +/- 0.18, P < 0.01) as compared with placebo (-0.03 +/- 0.12). Alfentanil and ketamine also increased RPTmuscle (0.25 +/- 0.21, P < 0.01 and 0.21 +/- 0.19, P < 0.05, respectively) as compared with placebo (0.00 +/- 0.17). Pain to IMES (AUCimes) was reduced (median values [25th-75th percentiles], cm x s) by alfentanil and ketamine (-19.7 [-14.6 - -29.6] and-12.8 [-8.3 - -27.8], P < 0.05, respectively) vs. placebo (-0.8 [1.6 - -12.3]). Similar drug effects were seen when pain to infusion of hypertonic saline (AUCsaline) was assessed (alfentanil:-388 [-99 - -677] and ketamine:-326 [-227 - -573], P < 0.05 compared with placebo: 150 [449--240]). Ketamine also reduced the size of the local pain area (-58.4 [-21.2 - -176.1], < 0.05) as compared with placebo (-0.4 [70.6 - -13.4]). The frequency of referred pain was also lower when ketamine was given (3/13, P < 0.05) vs. placebo (9/14).
The study demonstrates that experimental muscle pain induced in humans by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacological modulation similar to preclinical animal tests and clinical trials. The data suggest that these models can be valuable tools in analgesic drug development.
Patients with chronic pain after whiplash injury and fibromyalgia patients display exaggerated pain after sensory stimulation. Because evident tissue damage is usually lacking, this exaggerated pain perception could be explained by hyperexcitability of the central nervous system. The nociceptive withdrawal reflex (a spinal reflex) may be used to study the excitability state of spinal cord neurons. We tested the hypothesis that patients with chronic whiplash pain and fibromyalgia display facilitated withdrawal reflex and therefore spinal cord hypersensitivity. Three groups were studied: whiplash (n=27), fibromyalgia (n=22) and healthy controls (n=29). Two types of transcutaneous electrical stimulation of the sural nerve were applied: single stimulus and five repeated stimuli at 2 Hz. Electromyography was recorded from the biceps femoris muscle. The main outcome measurement was the minimum current intensity eliciting a spinal reflex (reflex threshold). Reflex thresholds were significantly lower in the whiplash compared with the control group, after both single (P=0.024) and repeated (P=0.035) stimulation. The same was observed for the fibromyalgia group, after both stimulation modalities (P=0.001 and 0.046, respectively). We provide evidence for spinal cord hyperexcitability in patients with chronic pain after whiplash injury and in fibromyalgia patients. This can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain, at least in part, pain in the absence of detectable tissue damage.
Unlabelled:
In the present study we investigated the effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine (30 mg/d) on the intensity of chronic phantom limb pain (PLP) and cortical reorganization. In 8 patients with chronic PLP, memantine was tested in a placebo-controlled double-blinded crossover trial of 4 wk duration per trial. The intensity of PLP was rated hourly by the patients on a visual analog scale during baseline and both treatment periods. At the same time points, the functional organization of the primary somatosensory cortex (SI) was determined by neuromagnetic source imaging. In comparison to baseline and placebo, the NMDA receptor antagonist had no effect on the intensity of chronic PLP. In none of the periods were significant changes in the functional organization of SI observed. Although the conclusions regarding the clinical effect are limited because of the small sample size, the data indicate that in the studied dosage the NMDA receptor antagonist memantine is ineffective in the treatment of chronic PLP and is also ineffective for the reduction of associated neural plasticity in the primary SI.
Implications:
NMDA receptors play a substantial role in central nervous system changes underlying neuropathic pain. In a placebo-controlled double-blinded study we tested the effect of 30 mg memantine on chronic phantom limb pain and pain-associated cortical reorganization.
Pain after amputation is common but difficult to treat. Therefore, the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain.
Forty-six patients scheduled to undergo lower limb amputation were randomly assigned to receive oral gabapentin or placebo. Treatment was started on the first postoperative day and continued for 30 days. The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day. The intensity of stump and phantom pain was recorded every day on a numeric rating scale (0-10) during the 30-day treatment period. Five interviews were performed after 7, 14, and 30 days and after 3 and 6 months.
Results from 41 patients were included in the data analysis. The risk of phantom pain (gabapentin vs. placebo) was 55.0% versus 52.6% (risk difference, 2.4%; 95% confidence interval, -28.9 to 33.7%; P = 0.88; 30 days) and 58.8% versus 50.0% (risk difference, 8.8%; 95% confidence interval, -23.3 to 40.9%; P = 0.59; 6 months). The median intensity of phantom pain (gabapentin vs. placebo) was 1.5 (range, 0-9.0) versus 1.2 (range, 0-6.6) (P = 0.60; 30 days) and 1.0 (range, 0-6.0) versus 0.5 (range, 0-5.0) (P = 0.77; 6 months). The median intensity of stump pain was 0.85 (range, 0-8.2) versus 1.0 (range, 0-5.4) (P = 0.68; 30 days) and 0 (range, 0-8.0) versus 0 (range, 0-5.0) (P = 0.58; 6 months).
Gabapentin administered in the first 30 postoperative days after amputation does not reduce the incidence or intensity of postamputation pain.
A placebo-controlled randomized crossover trial of the N-methyl-d-aspartic acid receptor antagonist, memantine , in patients with chronic phantom limb pain Electrophysiological and psychophysical quantification of central temporal summation of the human nociceptive system
- K Wiech
- Rt Kiefer
- S Topfner
- H Preissl
- Braun
- K Unertl
- Birbaumer H Flor
- L Nnielsen
- J Brennum
- S Sindrup
- Bak
Wiech K, Kiefer RT, Topfner S, Preissl H, Braun C, Unertl K, Flor H, Birbaumer N. A placebo-controlled randomized crossover trial of the N-methyl-d-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004;98:408 –13 16. Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of central temporal summation of the human nociceptive system. Eur J Appl Physiol 1994;68:266 –73
Analgesic effects of intravenous lidocaine and mor-phine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial
- Wu
- Tella P Cl
- Staats Ps
- R Vaslav
- Da Kazim
- U Wesselmann
- Sn
Wu CL, Tella P, Staats PS, Vaslav R, Kazim DA, Wesselmann U, Raja SN. Analgesic effects of intravenous lidocaine and mor-phine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology 2002; 96:841– 8
- Mikkelsen
Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers.
- Schulte
Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial.
- Wu