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Topical doxepin hydrochloride reduces neuropathic pain: A randomized, double-blind, placebo controlled study
Abstract
Tricyclic antidepressants have a proven efficacy in neuropathic pain but their use is frequently complicated by side-effects. In a randomized, double-blind, placebo controlled study we compared the effect of twice daily application of doxepin hydrochloride 5% and placebo in forty patients with neuropathic pain. Results were obtained from 75% of those enrolled. There was a significant reduction in pain scores (linear visual analogue scores, 0-10) in those treated with topical doxepin hydrochloride when compared to placebo (mean fall in doxepin group 1.18, P < 0.01). Minor side-effects were seen in 3 patients. There was no significant difference drowsiness levels in the two groups. We conclude that topical doxepin hydrochloride has an analgesic effect in neuropathic pain and its use is not commonly complicated by side-effects.
... Thus, tricylic antidepressants produce a peripherally mediated analgesia in preclinical models of ongoing and neuropathic pain, [10][11][12] and produce analgesia in human cases of neuropathic pain. 13,14 Peripheral excitatory amino acid receptor antagonists also might be useful in pain with a peripheral origin. 15 Thus, local injections of ketamine, which blocks N-methyl-D-aspartate (NMDA) receptors, produces analgesia in a preclinical model of ongoing pain, 16 and antihyperalgesic and some analgesic actions in human experimental models of inflammatory pain. ...
... Thus, 2 recent placebo controlled trials have demonstrated that topical doxepin, another tricyclic antidepressant, requires 2 weeks before significant pain relief occurs. 13,14 (Those studies were published during the course of the present trials.) In both of those studies, topical doxepin (5% and 3.3%, respectively) led to a significant reduction in overall pain scores in 40 13 and 200 14 patients with neuropathic pain. ...
... 13,14 (Those studies were published during the course of the present trials.) In both of those studies, topical doxepin (5% and 3.3%, respectively) led to a significant reduction in overall pain scores in 40 13 and 200 14 patients with neuropathic pain. The addition of capsaicin to doxepin produced an earlier onset of a significant response (1 week), but there was no augmentation of the degree of analgesia. ...
The involvement of ongoing peripheral activity in the generation of nociceptive input in neuropathic pain suggests that topical drug delivery may be useful as a treatment strategy. This is a pilot study providing initial information regarding the use of novel topical preparations containing amitriptyline (AMI), ketamine (KET), and a combination of both in the treatment of neuropathic pain.
The study design included a 2 day randomized, double blind, placebo controlled, 4 way cross-over trial of all treatments, followed by an open label treatment phase using the combination cream for 7 days. Twenty volunteers with chronic neuropathic pain were randomly assigned to treatment order and applied 5 mls of each topical treatment (1% AMI, 0.5% KET, combination AMI 1%/KET 0.5%, and placebo) for 2 days. Measures of pain at the end of each block included the short form McGill Pain Questionnaire (MPQ) and visual analog scales (VAS) for present pain intensity and pain relief. Eleven subjects who judged subjective improvement from any treatment in the initial trial entered the open-label trial and used the combination cream for 7 days. Pain levels were recorded daily using the same measures. Blood levels for amitriptyline and ketamine were performed at 7 days to determine whether systemic absorption had occurred.
There was no statistically significant difference from placebo after 2 days for any treatment during the double blind component of the trial. In the 11 subjects who used the combination cream, there was a statistically significant effect, with subjects reporting significantly greater analgesia by days 3 to 7 according to measures of pain and pain relief. Blood levels revealed that there was no significant systemic absorption of amitriptyline or ketamine. Only 2 subjects experienced side effects; these were minor and did not lead to discontinuation of the cream.
This pilot study demonstrated a lack of effect for all treatments in the 2 day double blind placebo controlled trial, followed by analgesia in an open label trial in a subgroup of subjects who chose to use the combination cream for 7 days. Blood analysis revealed no significant systemic absorption of either agent after 7 days of treatment, and creams were well tolerated. A larger scale randomized trial over a longer interval is warranted to examine further effects observed in the open label trial.
... This sodium channel blockade is one theory of how doxepin may also have pain control properties [83]. TCAs have long been used in chronic neuropathic pain, and the mechanism likely differs from the antidepressant effect; further, they also come with a host of side effects [84]. Doxepin for neuropathic pain has been investigated by few studies, and these all focused on its use in topical form. ...
... McCleane et al. studied topical doxepin to counter neuropathic pain while limiting adverse effects. They performed a randomized, double-blind, placebo-controlled study and found that topical doxepin significantly reduced neuropathic pain scores with minimal side effects [84,85]. De Leon-Casasola et al. also studied topical agents, including doxepin. ...
Chronic pain syndromes cost the US healthcare system over $600 billion per year. A subtype of chronic pain is neuropathic pain (NP), which is defined as “pain caused by a lesion or disease of the somatosensory system,” according to the International Association for the Study of Pain (IASP). The pathophysiology of neuropathic pain is very complex, and more research needs to be done to find the exact mechanism. Patients that have pre-existing conditions such as cancer and diabetes are at high-risk for developing NP. Many NP patients are misdiagnosed and are delayed treatment due to a lack of a standardized classification system that allows clinicians to identify, understand, and utilize pain management in these patients. Medications like tricyclic antidepressants, SNRI, and gabapentinoids are first-line treatments followed by opioids, cannabinoids, and other drugs. There are limited studies for the treatment of NP.
... Topical application of doxepin has been prescribed for the management of skin pruritus (5,9) and for neuropathic pain of the skin (5,10). We have previously reported pain relief following oral rinsing with doxepin suspension in patients with oral lesions due to cancer or treatment of cancer (11). ...
... Fatigue was reported later than the anesthetic effect, suggesting a local action resulting in anesthesia and a central action resulting in fatigue. Topical doxepin applied to the skin in areas of neuropathic pain has been shown to have good analgesic effect (9,10,17). Drowsiness has been reported following skin application (5). ...
Oral doxepin rinse has been reported to provide pain relief in patients with oral mucosal lesions due to cancer or cancer therapy. The purpose of this study was to assess the anesthetic effect of doxepin oral rinse in normal subjects to identify the duration of effect and to contrast the anesthetic effect with reported pain relief in patients with oral mucosal lesions. Normal volunteers were provided a solution of doxepin (5 mg/mL) for oral rinsing. Oral numbness and adverse effects were recorded for a period of 4 h after rinsing. Doxepin rinse resulted in mucosal anesthesia in all subjects. Sedation/fatigue was reported in four of seven subjects. There were no taste complaints and no nausea reported. The limited duration of numbness/anesthesia in normal subjects compared with prior studies showing pain relief for more than 3 h in patients with mucosal lesions, suggests that the extended duration of pain relief in patients was due to analgesic effects rather than anesthetic effects. The majority of normal subjects reported sedation after use, but this was less common in patients with mucosal lesions.
... T he involvement of peripheral mechanisms in the generation of neuropathic pain suggests that the use of topical approaches may be a useful treatment strategy. 12 Controlled clinical trials have demonstrated efficacy for topical capsaicin, 10,15 local anaesthetics, 3,4,11 and doxepin 8,9 in the treatment of neuropathic pain. In a previous pilot trial, we examined the analgesic effects of a topical cream containing 1% amitriptyline/ 0.5% ketamine. ...
... Randomized controlled trials have demonstrated that topical doxepin produces analgesia in a mixed group of patients with neuropathic pain 8,9 and that topical amitriptyline 4% in combination with ketamine 2% exhibits a significant analgesic effect in patients with postherpetic neuralgia. 5 A lower-dose cream containing 2% amitriptyline and 1% ketamine did not exhibit a statistically significant analgesic effect in a randomized controlled trial of patients with mixed diagnoses of neuropathic pain 7 ; however, post hoc analyses identified that the lower dose amitriptyline/ketamine cream may be analgesic in a subgroup of subjects with mixed neuropathic pain. ...
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Twenty eight subjects with refractory, moderate to severe peripheral neuropathic pain participated in an open label prospective trial examining perceived analgesic effect, patient satisfaction, and safety of topical amitriptyline 2%/ketamine 1% cream. Outcome measures included an 11-point numerical rating scale for pain intensity (NRS-PI), a 5-point satisfaction scale, blood chemistry screen, drug and metabolite levels, urinalyses, electrocardiogram (ECG), and physical examination. Adverse events were monitored. Twenty-one subjects completed the trial. At 6 months, subjects reported an average long-term reduction in pain of 34% (standard deviation [SD] = 37%); 5 subjects (25%) achieved 50% or greater reduction in pain and 1 subject (5%) achieved 100% reduction in pain. At 12 months, the average reduction in pain was 37% (SD = 40%); 7 subjects (40%) achieved 50% or greater pain reduction. At the end of the study, 89% of subjects rated their satisfaction as 3/5 or greater and 2 subjects (10%) were pain free. Minimal adverse events were reported and there were no serious medication related adverse events. Blood levels revealed minimal systemic absorption. In conclusion, topical 2% amitriptyline/ 1% ketamine cream was associated with long-term reduction (6-12 months) in perceived pain, moderate to complete satisfaction, and was well tolerated in treatment of neuropathic pain. There was no significant systemic absorption of amitriptyline or ketamine.
Perspective:
This study demonstrates that topical 2% amitriptyline/1% ketamine, given over 6-12 months, is associated with long-term perceived analgesic effectiveness in treatment of neuropathic pain. Antidepressants and ketamine both produce multiple pharmacologic effects that may contribute to peripheral analgesia; such actions include block of peripheral N-methyl-D-aspartate receptors, local anesthetic properties, and interactions with adenosine systems.
... Doxepin, a TCA, has been used in the treatment of major depression and other psychiatric disorders for longer than 40 years [1]. Recently, doxepin and other TCAs have also been used in the treatment of pain [2][3][4][5][6]15,16]. In animal studies, doxepin dose-dependently increased the mechanical pain threshold of the paw in rats [6]. ...
... In human studies, doxepin administered preoperatively significantly decreased postoperative opioid requirements [6]. Doxepin also effectively relieved lower back pain and neuropathic pain in patients [15,16]. Although doxepin was effective in alleviating pain, the detailed mechanism of its action is not clear [2]. ...
Doxepin, a tricyclic antidepressant, was recently found to be effective in the treatment of various acute and chronic painful conditions. However, the mechanism of its actions was not clear, especially when involving the spine. The aim of our study was to evaluate the spinal anesthetic effect of doxepin. Two commonly used traditional local anesthetics, bupivacaine and lidocaine, were used as controls. The potencies and durations of the drugs' action were evaluated in male Sprague-Dawley rats. We found that intrathecally administered doxepin, like bupivacaine and lidocaine, produced dose-related spinal anesthetic effects on motor activity, proprioception, and nociception. Among the three drugs, doxepin produced spinal anesthetic effects in rats more potent than that of lidocaine (p < 0.001, in each comparison) and longer than that of bupivacaine and lidocaine (p < 0.001, in each comparison). The spinal activity of doxepin may provide some explanation of its clinical effect in pain management.
... with potent H1 and H2 antagonistic properties, has been shown to have analgesic effects and has been useful in the treatment of skin pain, including in hidradenitis suppurativa and neuropathic pain. 19,29,30 It has been used in erythromelalgia with reported success in managing pain. 31 However, topical doxepin may cause localized burning and allergic contact dermatitis and drowsiness due to systemic absorption. ...
Erythromelalgia is a rare neurovascular disease that causes episodes of pain, redness, and warmth in the extremities, and can be debilitating. Currently, there is no universally effective treatment for erythromelalgia. As the precise etiology of erythromelalgia remains obscure, presently available treatments are aimed at alleviating erythromelalgia’s wide‐ranging symptoms. In general, topical therapies for erythromelalgia are preferred for their more limited side effects and for those with contraindications to systemic therapies. This review will summarize the current topical therapies available to treat erythromelalgia and discuss emerging therapies based on our growing understanding of erythromelalgia pathophysiology.
... Doxepin (DP) is commonly used in the treatment of psychiatric disorders such as depression, insomnia and anxiety (Flavia Laffleur, Martina Zilio, & Shuwisitkul, 2016;Kandagal, Seetharamappa, Ashoka, Shaikh, & Manjunatha, 2006). DP can block the reuptake of the neurotransmitters in the central nervous system and can be effective in the management of chronic neuropathic pain (McCleane, 2013;Randy A. Sansone & Sansone, 2008). The low doses of DP is promoting the initiation and maintenance of sleep (Haramandeep Singh & Becker, 2007;Juliane Weber, M. Asif A. Siddiqui, Antona J. Wagstaff, & McCormack, 2010). ...
In present work, molecularly imprinted nanoparticles (MINPs) were applied as selective adsorbent for ultrasound‐assisted micro‐solid phase extraction (UAMSPE) of doxepin (DP) from human plasma samples followed by high performance liquid chromatography (HPLC). The MINPs were synthesized based on noncovalent approach via precipitation polymerization utilizing methacrylic acid (MAA) and styrene (SY) as functional monomers, DP as template, ethylene glycol dimethacrylate (EGDMA) as cross‐linker, and 2,2‐azobisisobutyronitrile (AIBN) as initiator. The obtained MINPs were characterized by FT‐IR and FE‐SEM. Effective factors in the UAMSPE efficiency such as sonication time, volume of eluent solvent and amount of sorbent were investigated using central composite design and the optimum points were achieved as 4 min of sonication time, 380 μL of eluent solvent and 30 mg of sorbent. Under optimized conditions, the proposed method has linear responses in the range of 0.2–2000 ng mL‐1, with a satisfactory limit of detection (LOD) 0.04 ng mL‐1 and limit of quantification (LOQ) 0.11 ng mL‐1, respectively.
... In another study doxepin 5 % cream was topically evaluated. Results revealed significant pain reduction in doxepin group compared to the placebo [31]. Clinical trials have confirmed the effectiveness of lidocaine gel and patch dosage forms in neuropathic pain [32]. ...
A four-week, double-blind, randomized, placebo-controlled trial was conducted to assay the effectiveness of Ajwain 10 % (Trachyspermum ammi Sprague) topical cream on neuropathic pain. Intervention encompassed Ajwain 10 % and placebo creams. Ninety-two patients who specifically mentioned daily and nocturnal burning feet were randomly assigned to receive one of those interventions. Presence and decline in patients’ numbness, tingling and allodynia were also evaluated. Major outcome measure was alteration in feet burning intensity (final week versus baseline week) regarding to a visual analog scale on a 0–10 cm scale (0 being "no pain", 10 being "worst pain"). Significant reduction in feet burning scores as well as numbness, tingling and allodynia were found in Ajwain group compared to placebo. This trial examining a cream of Ajwain essential oil versus placebo revealed the significance difference between two groups. This medicament can be a good candidate for the alleviation of feet burning, a neuropathic complication.
... In another investigation, doxepin 5% cream was topically effective in reducing pain as compared to the placebo in a twice-daily application for 4 weeks. [70] ||CONCLUSION Management of neuropathic pain may be of challenge for physicians, and treatment with sole therapy may not be much beneficial and may rarely provide desirable outcome. However, administration of a single medication is often restricted due to dose-related side effects. ...
One of the most frequent problems in medical care is the management of patient presenting with chronic pain. Neuropathic pain is related to the injury or disorders affecting peripheral and central nervous systems and is resistant to over-the-counter analgesics and conventional treatment methods. The estimated prevalence for patients presenting classical symptoms of neuropathic pain is eventually reported to be 6%–8%. Several mechanisms have been considered and proposed for this disorder. The involvement of small and large sensory fibers as well as motor fibers is a reason for the presence of neuropathic pain. In addition to the lifestyle modification, a number of different therapeutic approaches and treatment protocols have been applied to control the neuropathic pain. However, management is still unsatisfactory. Comorbidities such as depression, anxiety, and sleep disorders are associated with this disorder and should be previously considered and eliminated. Analgesics, tricyclic antidepressants, anticonvulsant, serotonin– norepinephrine reuptake inhibitors, and local anesthetic agent as well as opioid analgesics and herbal medicaments such as capsaicin are known treatment lines for the management of neuropathic pain. Regarding the unsuccessfulness of single therapy, poly-pharmacy or combination therapy of two or more agents with synergistic mechanisms and different modes of action seems necessary.
... Moreover, it is preferred due to the close proximity of the delivery site to the localization of nerve endings in the dermal region. Doxepin is a tricyclic antidepressant that is known to exhibit analgesic effect in chronic neuropathic pain when applied topically [6][7][8][9]. However, topical delivery through skin is limited due to poor permeability of drugs and relatively longer lag times [10]. ...
The electroporation mediated transdermal delivery (Protocol - 120 V, 10 ms, 30 pulses at 1 Hz with post pulse waiting period of 20 min) of doxepin using pure drug solution (PDS) and doxepin-hydroxypropyl-beta-cyclodextrin (HPCD) complex solution (CDS) was studied using porcine epidermis model. The stoichiometry of drug-HPCD inclusion complex was determined by differential scanning calorimetry (DSC). The amount of doxepin retained in the epidermis following electroporation did not differ significantly between PDS and CDS. When the drug loaded epidermis was subjected to "Release studies", doxepin release attained a plateau within approximately 2.5 days in case of PDS, whereas in case of CDS, doxepin release was prolonged up to 5 days. Mechanistic studies across the nonbiological barriers demonstrated that the slow dissociation of complex was responsible for sustained release of drug from the epidermis. Pharmacodynamic studies were carried out by electroporation mediated delivery of CDS and PDS in hairless rats. The analgesic effect of doxepin was prolonged in case of CDS as compared to PDS.
... Analgesic properties after local peripheral administration of amitriptyline have been reported relatively recently in preclinical studies (13,20), and these observations have led to a consideration of the potential for administering amitriptyline as a topical analgesic in a clinical context (13,14,20). It is interesting to note that the topical application of another tricyclic antidepressant, doxepin, was recently reported to produce analgesia in humans with neuropathic pain (21,22). This study indicates that in conditions in which there is a clear peripheral afferent drive involved, the topical route might be very useful because of larger local drug concentrations, a more complete suppression of nociceptive behaviors and circuitry activated by nociceptive stimulation, and, potentially, fewer adverse effects, which can limit the effectiveness of oral preparations. ...
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We examined the effects of systemically, spinally, and peripherally administered amitriptyline on formalin-induced Fos immunoreactivity in the lumbar spinal cord. Formalin (2.5%), injected subcutaneously into the rat hindpaw, increased Fos immunoreactivity in laminae I-II, III-IV, and V-VI of the dorsal L5 spinal cord. Amitriptyline, administered both systemically and spinally before formalin, increased flinching and concurrently decreased biting/licking behaviors, but neither route of administration produced any statistically significant change in Fos immunoreactivity. Amitriptyline coadministered with the formalin reduced both flinching and biting/licking behaviors, and significantly reduced Fos immunoreactivity, particularly in laminae I-II. These immunohistochemical changes reflect the net behavioral effects observed after the different routes of drug administration. The profile of amitriptyline action after peripheral administration may be of clinical importance because of the potential use of antidepressants as topical analgesics.
Implications:
In the formalin test, amitriptyline produces different effects on pain behaviors after systemic, spinal administration and peripheral administration. Fos protein, an indicator of neuronal activity after noxious stimulation, is upregulated after formalin injection. We examined the effects of amitriptyline on such expression and observed a reduction in expression with peripheral administration.
... Thus, peripheral administration of ketamine produces analgesia in the rat formalin test (6; but see Ref. 7), whereas local administration of amitriptyline produces analgesia in the rat formalin test (8) in a neuropathic pain model (9) and in a cutaneous reflex model (10). In clinical reports, topical ketamine was reported to produce analgesia in case studies involving neuropathic and cancer pain (11,12), whereas topical doxepin, another tricyclic antidepressant, produced analgesia in placebo-controlled trials of neuropathic pain (13,14). Although these drugs exhibit promise as potential topical analgesics, the mechanistic basis of their peripheral actions is not well understood. ...
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In this study, we examined antihyperalgesic and analgesic actions after local peripheral administration of ketamine and amitriptyline in a rat model of mild thermal injury. Exposure of the hindpaw to 52 degrees C for 45 s under anesthesia produced a subsequent thermal hyperalgesia lasting at least 2 h. The local peripheral administration of ketamine (100-1000 nmol) 15 min before the thermal injury produced an antihyperalgesic effect when injected into the ipsilateral paw, whereas amitriptyline produced both antihyperalgesic (300 nmol) and analgesic (1000 nmol) effects. Administered after the thermal injury, ketamine had no effect, whereas amitriptyline retained its analgesic but not its antihyperalgesic effect. Amitriptyline (300 and 1000 nmol) produced an analgesic action when administered into the normal nonsensitized hindpaw. Both drugs increase paw volume, particularly at larger doses; biogenic amines are not involved in the action of amitriptyline, as was shown previously for ketamine. These results indicate that (a) ketamine produces antihyperalgesia, but not analgesia, when administered locally with a mild thermal injury model; (b) amitriptyline produces both antihyperalgesia and analgesia when administered locally; and (c) the increase in paw volume produced by these drugs occurs by different mechanisms.
Implications:
This study examines the pain-relieving properties of the local peripheral administration of ketamine and amitriptyline, two drugs in current clinical use, in a thermal injury model of hyperalgesia and demonstrates both antihyperalgesic and analgesic properties. These observations provide support for their potential use as local (e.g., topical) analgesics.
Chronic pain is one of the most common reasons for patients to seek medical care. There are numerous ways in which this pain can be addressed through medication. Chronic pain is difficult to treat as conditions that can cause pain are not uniform and cases are not always responsive to specific treatments. Currently, there is great interest in providing pharmaceutical analgesia without the use of opioid medications. Generally, pain can be divided into nociceptive and neuropathic. Within those categories, certain medications remain first line and have been shown to be effective with multiple studies. There are other less-established options that can be used as alternatives or adjuncts. The aim of this chapter is to provide examples of treatment options that have been supported by research and evidence, as well as to highlight options that are emerging.
A 17-year-old female with recently relapsed acute lymphoblastic leukaemia and a treatment course complicated by rhinocerebral mucormycosis infection developed severe peripheral neuropathy during the treatment for mucormycosis infection. This was felt to be a medication side effect. Her peripheral neuropathy was refractory to many well-established treatments, but ultimately responded dramatically and consistently to a novel therapy, topical doxepin cream (5%). This case report is the first published report of the application of topical doxepin cream for treatment of peripheral neuropathy in a paediatric patient.
Cancer pain considered as neuropathic can occur in up to 40% of cancer patients and impair quality of life. Neuropathic cancer pain is treated using therapies with proven efficacy in other neuropathic pain (NeP) conditions including adjuvants such as tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, gabapentinoids, and other agents. Topical analgesics are often considered as adjuvant analgesics or co-analgesics to use for cancer pain. While there are a limited number of clinical trials using topical analgesics for NeP related to cancer, there has been some exploration of this indication. We reviewed the various categories of topical analgesics in relation to cancer care such as lidocaine medicated plaster, topical capsaicin, topical opioids and so on.
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is an active component of chilli peppers. It binds to TRPV1 (transient receptor potential channel) receptors which is a heat-activated calcium channel. It causes depletion of substance P and decrease the density of epidermal nerve fibres. The effect takes 3–4 weeks to manifest. It is available in 0.025 %, 0.075 % cream and 8 % patch. 0.075 % cream applied 3–4 times/day has shown efficacy in painful diabetic neuropathy and postherpetic neuralgia (NNT for 50 % pain relief is 6.7). It is associated with burning sensation which can be reduced by co-administration of glyceryl trinitrate or EMLA (eutectic mixture of local anaesthetics).
Pain management is a vast subject and is changing rapidly. Finding a good resource for learning, however, is difficult. This book covers the entire curriculum relating to pain management and will make it easy to learn all aspects of the subject by covering key concepts in a reader-friendly manner. It comprises nine concise and simple chapters that aim to impart the maximum information within a limited space. These chapters address anatomy, assessment of pain, diagnosis of pain, pharmacology, non-pharmacological pain management, acute and chronic pain management, pain management in special groups, and special techniques. Pain Management: Essential Topics for Examinations will be an ideal resource for those who plan to sit for examinations, wherever they are based in the world. In addition, it will be an invaluable reference for higher and advanced pain trainees, residents, and physicians working in chronic pain.
Objective: To evaluate the potential role of tramadol treatment with respect to CYP2D6 polymorphism in reducing the incidence of adverse drug reactions.
Diabetes, a silent killer, is a leading cause of neuropathy. Around 50% of diabetic patients develop peripheral neuropathy in 25 years. Painful diabetic neuropathy manifests as burning, excruciating, stabbing or intractable type of pain or presents with tingling or numbness. The pathophysiology of this condition is due to primarily metabolic and vascular factors. There is increase in sorbitol and fructose, glycated endproducts, reactive oxygen species and activation of protein kinase C in the diabetic state. All these factors lead to direct damage to the nerves. The first step in the management of painful diabetic neuropathy is a tight glycaemic control. Currently there is no drug which can halt or reverse the progression of the disease. Most of the therapies prevalent aim at providing symptomatic relief. Antidepressants like tricyclic antidepressants (TCAs) and selective norepinephrine reuptake inhibitors (SNRIs) have good efficacy in controlling the symptoms. Selective serotonin reuptake inhibitors have not shown the same consistent results. Anticonvulsants including pregabalin, gabapentin and lamotrigine have shown good results in the control of symptoms whereas same was not found with carbamazepine, oxcarbazepine and topiramate. Topical agents (capsaicin, topical nitrates and topical TCAs) and local anaesthetics have also been used with good results. Use of opioids and non steroidal anti-inflammatory drugs although common but is not preferable. The newer therapies under studies are NMDA antagonists, aldose reductase inhibitors, neurotropic factors, vascular endothelial growth factor, Gamma linolenic acid, protein kinase C beta inhibitors, immune therapy, hyperbaric oxygen and alpha lipoic acid.
Hidradenitis Supprurativa (HS) is a painful chronic follicular disease. Few papers have addressed pain control for this debilitating condition. Possible topical agents include tricyclic antidepressants, opioids, anticonvulsants, NSAIDs, NMDA receptor antagonists, local anesthetics and other agents. The first line agents for the topical treatment of the cutaneous pain of HS are diclonefac gel 1% and liposomal xylocaine 4% and 5% cream or 5% ointment. The chief advantage of topical xylocaine is that is quick acting i.e. immediate however with a limited duration of effect 1-2 hours. The use of topical ketamine, which blocks n-methyl-D-aspartate receptors in a non-competitive fashion, might be a useful tool for the treatment of HS pain. Topical doxepin, which available in a 5% commercially preparation (Zonalon®) , makes patients drowsy and is not useful for controlling the pain of HS . Doxepin is available in a 3% or 3.3% concentration (which causes less drowsiness) from compounding pharmacies and can be used in compounded analgesic preparations with positive effect. Topical doxepin is preferred over use of topical amitriptyline because topical doxepin is more effective. Nevertheless, topical amitriptyline increase of the tactile and mechanical nociceptive thresholds and can be used for topical pain control in compound mixture of analgesics . Gabapentin and pregablin can also be used compounded with other agents in topical analgesic preparations with positive topical anesthetic effect. Capsaicin is not useful for topical treatment of the pain of HS. Sometimes compounded of anesthetics medications such as ketamine 10%, bupivacaine 1%, diclofenac 3%, doxepin 3% or 3.3%, and gabapentin 6% can extend the duration of effect so that medication only needs to be used 2 or 3 times a day. Still in my experience the easiest to get and most patient requested agent is topical diclonefac 1% gel.
Topical analgesics applied locally to skin or to specialized compartments modify pain by actions on sensory nerve endings and/or adjacent cellular elements. With this approach, there are low systemic drug levels, good tolerability and few drug interactions, and combination with oral formulations is feasible. The goal of this review is to provide an overview of the potential for topical analgesics to contribute to improved management of neuropathic pain. Mechanistic and preclinical studies indicate much potential for development of novel topical analgesics for neuropathic pain. In humans, two topical analgesics are approved for use in post-herpetic neuralgia (lidocaine 5% medicated plaster, capsaicin 8% patch), and there is evidence for efficacy in other neuropathic pain conditions. Comparative trials indicate similar efficacy between topical and oral analgesics. Not all individuals respond to topical analgesics, and there is interest in determining factors (patient factors, sensory characteristics) which might predict responsiveness to topical analgesics. There is a growing number of controlled trials and case reports of investigational agents (vasodilators, glutamate receptor antagonists, α2-adrenoreceptor agonists, antidepressants, centrally acting drugs), including combinations of several agents, indicating these produce pain relief in neuropathic pain. There is interest in compounding topical analgesics for neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of neuropathic pain.
The prevalence of neck pain disorders is increasing worldwide. Approximately 10% of adult have neck pain at any one time and less than 1% develop neurological deficit. The treatment of neck pain depends on its precise cause. It includes: rest, heat/ice application, traction, soft collar traction, physical therapy, transcutaneous electric nerve stimulation, surgical procedures and pharmacotherapy. The current pharmacological agents that used in management of neck pain include: non steroidal anti-inflammatory drugs, centrally acting analgesia, acetaminophen, muscle relaxants, topical painkillers and/or topical anesthesia, local steroids and/or local anesthetics injections and antimicrobials. This review focuses on the concepts of pharmacotherapy of neck pain disorders in respect to the cause of neck pain, the nature of pain (acute, chronic, neuropathic or nociceptive), the mechanism of drug action, the practice of local injections with radiologist intervention, quality of life and the long term harmful effects including medicines abused. Also this review describes the beneficial effect of tumor necrosis factor-alpha (TNF-α) blockers, calcitonin gene related peptide antagonists, antimicrobials particularly in infectious cervical discitis and the traditional medicines including natural plants and herbs.
Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com).
At times providing pain relief in elderly patients can prove troublesome. Their tolerance and perception of pain can differ from that of younger patients, while the incidence of pain is above that found in those of less advanced years.
Conventional approaches to providing pain relief can be successful, but the tolerance to the side-effects of those drugs used to provide pain relief can be less. Furthermore, polypharmacy can have implications for the range of analgesic drugs that can be considered. Fortunately there are an increasing range of medicinal products with reduced potential for side-effects that can be considered when treating older patients with pain.
Objective: To evaluate the safety and efficacy of oral tramadol therapy (50 to 200 mg/day) in the treatment for post-herpetic neuralgia (PHN).
Methods: The study was a prospective, single-blind, non-responder vs. responder, randomized trial conducted in 100 outpatients of PHN after oral administration of tramadol for 4 weeks. Those patients who had achieved 50% or greater pain relief after 14 days of oral tramadol treatment were categorized as responders and those reporting < 50% pain relief were categorized as non-responders. Rescue analgesia was provided by the topical application of a cream consisting of the combination of 3.33% doxepin and 0.05% capsaicin to the affected areas of PHN patients of both groups for at least 14 days, along with tramadol therapy. The rescue analgesia was extended to 4 weeks in patients of the non-responder group. The primary endpoints were measured using a Numerical Rating Scale (NRS) at rest and with movement. Secondary endpoints included additional pain ratings such as global perceived effect (GPE), Neuropathic Pain Symptom Inventory scores (NPSI), daily sleep interference score (DSIS), Quality of life (QOL) as per WHO QOL-BREF Questionnaire scores, patient and clinician ratings of global improvement. The 2 groups were compared on the basis of pain intensity scores, encompassing primary as well as secondary endpoints, and QOL after 28 days of the treatment regimen.
Results: Pain intensity scores measured by NRS (at resting and with movement), NPSI, and DSIS were consistently reduced (P < 0.001) over 28 days at varying intervals in both the groups, but the magnitude of reduction was higher in responders than non-responders. A concomitant improvement (P < 0.001) was observed in GPE on days 3, 14, and 28 as compared to the respective baseline scores in both the groups. Although the WHO QOL-BREF scores showed significant (P < 0.001) improvement in QOL of PHN patients at days 14 and 28 in both the groups, the magnitude of improvement was higher in responders as compared to non-responders. Significant improvement in pain intensity scores and QOL in non-responders is mainly attributed to the use of rescue analgesia for 28 days rather than recommended tramadol therapy.
Conclusions: Treatment with tramadol 50 to 200 mg per day was associated with significant pain reduction in terms of enhanced pain relief, reduced sleep interference, greater global improvement, diminished side-effect profile, and improved QOL in PHN patients from North India. Further categorization of PHN patients may be helpful so that additional or alternative therapy may be prescribed to non-responders.
Topical analgesics are applied to the skin and produce a localized effect on sensory nerve endings to inhibit pain signaling in the periphery. This approach offers the advantage of few systemic adverse effects. There is clear evidence that topical NSAIDs produce analgesia, especially in osteoarthritis. Topical local anesthetics produce pain relief in post-herpetic neuralgia and focal neuropathies. Both classes of drug have entered treatment algorithms as early treatment options. Topical capsaicin produces analgesia in neuropathic pain, but use is limited by local adverse effects and it is considered a third-line treatment. There is less evidence for benefit from rubefacients in chronic pain. Opioids exhibit peripheral analgesia with arthroscopic knee surgery and chronic knee inflammation conditions, and topical applications appear promising for wounds and oral mucosa lesions. The realm of topical analgesics is receiving considerable attention, and several novel targets are being explored for efficacy.
Tricyclic antidepressants (TCA) have potent local anesthetic properties and may produce a long-lasting pain blockade that could be of interest in relieving chronic pain states such as neuropathic pain, but there are only few data comparing their dose-response curves of analgesic activity under the same experimental conditions. This study examines the time course of pain-relieving properties of 7 TCA in heat-induced paw withdrawal after subcutaneous administration. Mixed inhibitors of norepinephrine and serotonin uptake (amitriptyline, nortriptyline, imipramine, desipramine, doxepin) and selective inhibitors of serotonin uptake (fluoxetine and fluvoxamine) were assayed. The TCA with the longest analgesic activity were selected to test its antiallodynic effect in the neuropathic pain model of chronic sciatic nerve constriction injury. Bupivacaine was used as a reference drug in both experiments. A dose versus time of maximal analgesic effect curve was constructed for each drug. The longest analgesic effect was obtained for doxepin and imipramine. Although low doses of amitriptyline showed the same activity than doxepin, higher doses failed to reach the same effect. Selective inhibitors of serotonin showed no action at all doses tested. In the chronic sciatic nerve constriction injury model, doxepin and, to a smaller degree, amitriptyline and imipramine protected from allodynia; bupivacaine was ineffective. The antiallodynic effect always lasted less long than the analgesic effect. These observations provide support for the potential use of TCA as durable analgesics. Doxepin overall showed the most outstanding results in pain relief.
To assess the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3. 3% doxepin and 0.025% capsaicin in human chronic neuropathic pain.
A randomized, double-blind, placebo-controlled study of 200 consenting adult patients. Patients applied placebo, doxepin, capsaicin or doxepin/capsaicin cream daily for 4 weeks. Patients recorded on a daily basis overall pain, shooting, burning, paraesthesia and numbness using a 0-10 visual analogue scale during the week prior to cream application (baseline levels) and for the 4 week study period. Side-effects and desire to continue treatment were also recorded.
Overall pain was significantly reduced by doxepin, capsaicin and doxepin/capsaicin to a similar extent. The analgesia with doxepin/capsaicin was of more rapid onset. Capsaicin significantly reduced sensitivity and shooting pain. Burning pain was increased by doxepin and by capsaicin and to a lesser extent by doxepin/capsaicin. Side-effects were minor. One patient requested to continue placebo cream, 17 doxepin cream, 13 capsaicin and 9 the combination of doxepin and capsaicin.
Topical application of 3.3% doxepin, 0.025% capsaicin and 3.3% doxepin/0. 025% capsaicin produces analgesia of similar magnitude. The combination produces more rapid analgesia.
Antidepressants, given systemically, are widely used for the treatment of various chronic and neuropathic pain conditions in humans. In animal studies, antidepressants exhibit analgesic properties in nociceptive, inflammatory and neuropathic test systems, with outcomes depending on the specific agent, the particular test, the route of administration and the treatment method used. Although early studies focused on central (i.e., supraspinal, spinal) actions, more recent studies have demonstrated a local peripheral analgesic effect of antidepressants. These peripheral actions raise the possibility that topical formulations of antidepressants may be a useful alternative drug delivery system for analgesia. Antidepressants exhibit a number of pharmacological actions: they block reuptake of noradrenaline and 5-hydroxytryptamine, have direct and indirect actions on opioid receptors, inhibit histamine, cholinergic, 5-hydroxytryptamine and N-methyl-D-aspartate receptors, inhibit ion channel activity, and block adenosine uptake. The involvement of these mechanisms in both central and peripheral analgesia produced by antidepressants is considered. Data illustrating the preclinical peripheral analgesic actions of antidepressants are presented, as are some aspects of the mechanisms by which these actions occur.
Oral mucositis is a treatment limiting toxicity of cancer therapy. The purpose of this study was to assess the impact of doxepin oral rinse in the management of oral mucosal pain in cancer patients. Forty-one cancer patients with oral mucosal pain were provided a solution of doxepin (0.5%) for oral rinsing. Oral pain was assessed prior to rinsing, and following rinsing for 4 h using a visual analogue scale (VAS). Adverse effects were recorded. Doxepin rinse resulted in a reduction of pain intensity of more than 50%, with pain relief extending for more than 3 h with pain not returning to baseline 4 h after rinsing. The rinse was tolerated by patients with mucosal damage, and had acceptable taste, and infrequent mucosal stinging with use. Some patients reported sedation after use, likely due to systemic absorption. The results of this single dose trial suggest that topical doxepin rinse has significant ability to provide clinically significant pain relief in patients with mucosal damage with an extended duration of effect.
Acute nociceptive, inflammatory, and neuropathic pain all depend to some degree on the peripheral activation of primary sensory afferent neurons. The localized peripheral administration of drugs, such as by topical application, can potentially optimize drug concentrations at the site of origin of the pain, while leading to lower systemic levels and fewer adverse systemic effects, fewer drug interactions, and no need to titrate doses into a therapeutic range compared with systemic administration. Primary sensory afferent neurons can be activated by a range of inflammatory mediators such as prostanoids, bradykinin, ATP, histamine, and serotonin, and inhibiting their actions represents a strategy for the development of analgesics. Peripheral nerve endings also express a variety of inhibitory neuroreceptors such as opioid, alpha-adrenergic, cholinergic, adenosine and cannabinoid receptors, and agonists for these receptors also represent viable targets for drug development. At present, topical and other forms of peripheral administration of nonsteroidal anti-inflammatory drugs, opioids, capsaicin, local anesthetics, and alpha-adrenoceptor agonists are being used in a variety of clinical states. There also are some clinical data on the use of topical antidepressants and glutamate receptor antagonists. There are preclinical data supporting the potential for development of local formulations of adenosine agonists, cannabinoid agonists, cholinergic ligands, cytokine antagonists, bradykinin antagonists, ATP antagonists, biogenic amine antagonists, neuropeptide antagonists, and agents that alter the availability of nerve growth factor. Given that activation of sensory neurons involves multiple mediators, combinations of agents targeting different mechanisms may be particularly useful. Topical analgesics represent a promising area for future drug development.
In health, the nervous system exists in a balance between inhibitory and excitatory influences. This balance may be upset if neural tissue is damaged or irritated and may give rise to neuropathic pain. Such neuropathic pain does not respond consistently to opioid analgesics or NSAIDs and it may therefore be necessary to utilise other therapeutic agents with known activity on either the excitatory or inhibitory components of the pain pathway. These other agents are traditionally considered with reference to their original uses; we still refer to tricyclic antidepressants (TCAs) and anticonvulsant drugs when a consideration of their modes of action may allow more rational use. For example, carbamazepine is related to the TCAs by virtue of its chemical structure and proposed mode of action and yet is still classified as an anticonvulsant drug.
With respect to the opioids, increasing evidence points to an analgesic effect in neuropathic pain, although concerns regarding tolerance and dependence still prevent more widespread use. The anticonvulsants comprise a group of compounds possessing anticonvulsant and analgesic properties, but each possesses differing modes of action and so several members of the class should be tried before a conclusion is reached that they, as a whole, are ineffective. TCAs may also have a role in the treatment of neuropathic pain. As with all drugs, if their use is not associated with pain relief in a defined period of time, their use should be terminated. Topical TCAs may also have a role where the area of neuropathic pain is small. Other options, such as SSRIs, membrane stabilisers, capsaicin, baclofen and clonidine may have potential in treating neuropathic pain.
The available evidence regarding the efficacy of currently available agents for the treatment of neuropathic pain is sparse. With the knowledge of achieving analgesia, according to the modes of actions of various agents it is hoped that the treatment of this difficult condition may be more logical and successful.
Unlabelled:
Among various tricyclic antidepressants, doxepin and amitriptyline are also long-acting local anesthetics. We synthesized a new compound, N-methyl doxepin, and investigated whether this derivative possesses local anesthetic properties. N-methyl doxepin and doxepin were tested in a rat sciatic nerve model at 2.5, 5.0, and 10 mM. Proprioceptive, motor, and nociceptive blockade were evaluated and compared with those induced by 0.5% bupivacaine. Block of Na(+) channels by N-methyl doxepin and doxepin was assessed in cultured pituitary tumor cells under voltage clamp conditions. N-methyl doxepin elicited complete nociceptive blockade that generally lasted longer than that caused by doxepin (e.g., approximately 7.4 h versus 5.3 h at 10 mM). Significant differences were observed for full recovery of function at all concentrations and for the duration of complete blockade except at 2.5 mM. Bupivacaine at 0.5% (15.4 mM) was less effective in producing complete blockade (approximately 1.5 h) than N-methyl doxepin and doxepin. Both doxepin and N-methyl doxepin were potent Na(+) channel blockers, although N-methyl doxepin displayed a slower wash-in rate. No morphological alterations were detected in cross-sectioned sciatic nerve specimens with these three drugs. We conclude that N-methyl doxepin is a potent Na(+) channel blocker and a long-acting local anesthetic for rat sciatic nerve blockade.
Implications:
N-methyl doxepin and doxepin are both potent Na(+) channel blockers; they elicit rat sciatic nerve block lasting longer than that induced by bupivacaine and seem to be nontoxic to peripheral nerves at concentrations up to 10 mM.
The pharmacological treatment of neuropathic pain relies, to a large extent, on drugs belonging to a small number of defined classes. Opioids, tricyclic antidepressants, antiepileptic drugs and membrane stabilisers form the current basis of treatment. Varying levels of evidence support the use of individual members of these classes and overall show no indication that one class of drug, or individual drug has universal effectiveness. More refined knowledge of the modes of action of these agents used to treat neuropathic pain should lead to a more logical approach to the management of this difficult series of conditions. A number of drugs currently licensed for a different indication have recently had an analgesic effect in neuropathic pain attributed to them. In addition, a number of novel compounds are undergoing investigation and provide hope of dicovering more efficacious treatment options in the future.
The aim of this article is to highlight a novel treatment for the symptoms of chronic urethral and trigonal irritation. A patient with severe urethral hyperaesthesia who derived almost complete alleviation of symptoms with topical application of a tricyclic antidepressant cream is described. The possible modes of action of tricyclics when used via the topical route of administration are described. Topical application of a tricyclic antidepressant cream may alleviate the symptoms of urethral hyperaesthesia.
The local, peripheral administration of antidepressants and excitatory amino acid receptor antagonists can cause analgesia in a number of conditions. The present study examined the effects of combinations of dextromethorphan and ketamine, two clinically used N-methyl-D-aspartate (NMDA) receptor antagonists, with amitriptyline on formalin-evoked behaviors and paw edema. Pretreatment with amitriptyline or dextromethorphan (10-300 nmol) resulted in suppression of flinching behaviors induced by 2.5% formalin, but ketamine had no intrinsic effect. Combination of an inactive dose of dextromethorphan with amitriptyline, and vice versa, resulted in an increase of analgesia so that previously inactive doses now caused significant analgesia. Combinations of multiple doses of ketamine with amitriptyline did not modify the response to amitriptyline. Both dextromethorphan and ketamine increased the paw edema induced by formalin, and this was blocked by low doses of amitriptyline. In the absence of formalin, amitriptyline (1-100 nmol) caused a dose-related suppression of the paw edema produced by dextromethorphan and ketamine. Amitriptyline also blocked paw edema produced by 5-hydroxytryptamine and compound 48/80. Each of the drugs used in this study exerts multiple pharmacological effects. Increased analgesia by drug combinations (amitriptyline/dextromethorphan) could show the involvement of a number of these mechanisms (e.g. NMDA receptor blockade, blockage of sodium channels, blockage of biogenic amine receptors), while a lack of intensification (amitriptyline/ketamine) could reflect occluded actions due to expression of similar actions by the other drug. Paw edema induced by dextromethorphan and ketamine involves inhibition of biogenic amine reuptake, and the ability of amitriptyline to block biogenic amine receptors likely accounts for its inhibiton of these actions. Combinations of these particular agents could represent a method for augmented analgesia and minimization of local adverse reactions.
A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain.
Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction.
A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered.
This randomized, placebo-controlled trial examining topical 2% amitriptyline, 1% ketamine, and a combination in the treatment of neuropathic pain revealed no difference between groups. Optimization of doses may be required, because another study has revealed that higher concentrations of these agents combined do produce significant analgesia.
Neuropathic pain can be difficult to treat clinically, as current therapies involve partial effectiveness and significant adverse effects. Following the development of preclinical models for neuropathic pain, significant advances have been made in understanding the neurobiology of neuropathic pain. This includes an appreciation of the molecular entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and the contribution of inflammation. Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available for treating neuropathic pain in humans. Preclinical studies provide evidence that peripheral applications of opioids, alpha-adrenergic agents, and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide support for topical applications of such agents. An appreciation of the ability of drug application, to sites remote from the site of injury, to alleviate aspects of neuropathic pain will provide a significant impetus for the further development of novel topical analgesics for this condition.
The past two decades have contributed a large body of preclinical work that has assisted in our understanding of the underlying pathophysiological mechanisms that cause chronic pain. In this context, it has been recognized that effective treatment of pain is a priority and that treatment often involves the use of one or a combination of agents with analgesic action. The current review presents an evidence-based approach to the pharmacotherapy of chronic pain. Medline searches were done for all agents used as conventional treatment in chronic pain. Published papers up to June 2005 were included. The search strategy included randomized, controlled trials, and where available, systematic reviews and meta-analyses. Further references were found in reference sections of papers located using the above search strategy. Agents for which there were no controlled trials supporting efficacy in treatment of chronic pain were not included in the present review, except in cases where preclinical science was compelling, or where initial human work has been positive and where it was thought the reader would be interested in the scientific evidence to date.
In recent years, tricyclic antidepressant drugs have experienced a resurgence in their use as valuable pharmacological tools in the treatment of pain. Along with the evolution in our understanding of their analgesic mechanisms of action, there have been concurrent breakthroughs regarding their indications for use and modes of administration. This review focuses on recent advances in our understanding of how antidepressant drugs exert their antinociceptive effects, and new developments regarding their clinical application.
Medicines used to treat depression are also effective in treating neuropathic pain A number of medicines used to treat depression (antidepressants) are effective in treating pain associated with nerve damage (neuropathic pain). We found that two-thirds of patients with neuropathic pain who took traditional antidepressants (such as amitriptyline) obtained at least moderate pain relief. However, approximately one fifth found the side effects unacceptable. There is limited evidence that the newer antidepressants, known as SSRIs, are effective. Neuropathic pain can be treated with antidepressants and the effect is independent of any effect on depression .
Historically, analgesics were applied by the topical route of administration. With the advent of oral formulations of drugs, topical application became less popular among physicians, although patients still rated this method of drug delivery as efficacious and practical. We now appreciate that peripheral mechanisms of actions of a variety of preparations rationalizes their topical application and gives further opportunity to target peripheral receptors and neural pathways that previously required systemic administration to achieve therapeutic effect. Therefore, a peripheral effect can be generated by using locally applied drug and, consequently, systemic concentrations of that drug may not reach the level at which systemic side effects can occur.
Depression is a common accompaniment of pain, particularly when pain is unremitting. The use of a variety of antidepressant medications is associated with pain reduction, an effect that is independent of the mood-enhancing qualities of these drugs. This pain relief is a consequence of a wide variety of actions of antidepressants on the neuroregulatory mechanisms associated with pain perception and transmission.
The older tricyclic antidepressants (TCAs) and the newer ‘balanced’ reuptake inhibitors (such as duloxetine) seem to be more efficacious in terms of providing pain relief than the selective serotonin reuptake inhibitors. Unfortunately, adverse effects are not uncommon during antidepressant use, particularly with TCAs. It is now becoming apparent that TCAs can have an analgesic effect when applied topically and that this effect is produced by peripheral mechanisms rather than systemic uptake.
Antidepressants remain a major therapeutic tool in the management of chronic pain.
Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective.
We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period.
After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients.
Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.
Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressant agents, but its pain-relieving potential has received little study. Other antidepressant agents--notably amitriptyline--are known to ameliorate postherpetic neuralgia, but those agents are often toxic. In a randomized double-blind crossover design, we gave 26 postherpetic neuralgia patients 6 weeks of treatment with desipramine (mean dose, 167 mg/day) and placebo. Nineteen patients completed both treatments; 12 reported at least moderate relief with desipramine and two reported relief with placebo. Pain relief with desipramine was statistically significant from weeks 3 to 6. Psychiatric interview at entry into the study produced a diagnosis of depression for 4 patients; pain relief was similar in depressed and nondepressed patients and was statistically significant in the nondepressed group alone. We conclude that desipramine administration relieves postherpetic neuralgia and that pain relief is not mediated by mood elevation. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressant agents that have relieved neuropathic pain, may be involved in relief of postherpetic neuralgia.
A single-blind imipramine dose titration study was conducted in 15 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by use of visual analog scales. Imipramine doses were individually adjusted until doses yielded plasma concentrations of imipramine plus desipramine that were well above 400 nmol/L or until all neuropathy symptoms had vanished. In all except one patient, there was marked relief of symptoms. In the responding patients (n = 14), much of the effect occurred at plasma levels of imipramine plus desipramine below 100 nmol/L, but a considerable interindividual variation was observed. Concentrations above 400 to 500 nmol/L were required to ensure maximal effect in all patients, and we did not find any indication of a decreased effect at high drug levels. The dose-dependent kinetics of imipramine was confirmed, and dose increments should therefore be carried out in small steps and preferably with monitoring of drug levels.
Twelve patients with severe, painful diabetic neuropathy in the lower extremities were treated with imipramine and placebo in a fixed-dose, double-blind, crossover study of five plus five weeks. Seven patients experienced notable improvement while receiving imipramine and none while receiving placebo. The rating of specific symptoms at the end of each treatment period showed a beneficial effect of imipramine on pain, paresthesia, dysesthesia, numbness, and nocturnal aggravation. The plasma levels of imipramine and its metabolite desipramine were significantly higher in patients who benefited from imipramine treatment.
(JAMA 1984;251:1727-1730)
This retrospective study was designed to assess the effects of acyclovir treatment of acute herpes zoster on subsequent postherpetic neuralgia, and to examine the effects of amitriptyline in the treatment of postherpetic neuralgia. Eighty seven patients with postherpetic neuralgia of three or more months' duration were studied: 24 of them had had their herpes zoster treated with oral acyclovir. At first presentation, only 25% of the 24 patients who had had their herpes zoster treated with acyclovir selected the word group containing burning on the McGill pain questionnaire compared with 76% of the 63 patients who had not received acyclovir. A higher proportion of patients who had had acyclovir than had not selected the word group which contains the word aching (63% versus 49%). Acyclovir thus appears to change the nature of postherpetic neuralgia. Postherpetic neuralgia was treated with amitriptyline, alone or in combination with distigmine and/or sodium valproate. There was a strong correlation between pain relief and the interval between the occurrence of herpes zoster and the initiation of treatment with amitriptyline--early treatment is almost twice as likely to be successful as late. Since conventional analgesics and sympatholytic drugs are of no benefit in the treatment of established postherpetic neuralgia, the sequelae of herpes zoster must, therefore, be recognized and treated with amitriptyline as soon as possible.
Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.
Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.
1. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day-1 of both drugs. Nineteen patients completed the study. 2. Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nM in extensive metabolisers, vs 590 and 750 nM in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3. Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer- and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl-clomipramine less than 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4. Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5. Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.
In a randomized, double-blind crossover study, 29 patients with painful diabetic neuropathy received 6 weeks of amitriptyline and 6 weeks of an "active" placebo that mimicked amitriptyline side effects. Amitriptyline was superior to placebo in relieving pain in weeks 3 through 6. Both steady, burning pain and lancinating pains were relieved. Patients able to tolerate higher amitriptyline doses reported greater relief, through the maximum dose of 150 mg nightly. Amitriptyline analgesia was similar in depressed and nondepressed subgroups and was not associated with mood improvement. We conclude that amitriptyline relieves pain in diabetic neuropathy; this effect is independent of mood elevation.
A double-blind, 3-phase, cross-over, placebo-controlled trial of the pain-relieving effect of amitriptyline and carbamazepine was carried out in 15 patients with central post-stroke pain (CPSP) but without signs of depression. Treatment was given, in randomized order, for periods of 4 weeks, separated by 1 week wash-out. The final doses were 75 and 800 mg/day, respectively, for amitriptyline and carbamazepine. The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale. For the assessment of depression the Comprehensive Psychopathological Rating Scale (CPRS) was used. Amitriptyline produced a statistically significant reduction of pain when compared to placebo. According to the global rating, 10 of the 15 patients were responders to this drug. The effect could already be noticed during the second treatment week and it appeared to be correlated to the plasma concentration, since the median total ami- and nortriptyline concentrations were 497 and 247 nmol/l, respectively, for responders and non-responders. The early onset, together with the fact that the patients were not depressed, nor did they obtain reduced scores on ratings of depressive symptoms and signs, provides strong support for the conclusion that the pain relief was not caused by an antidepressive effect. Five of the 14 patients treated with carbamazepine reported some pain relief, but the effect did not reach statistical significance when compared to placebo. No correlation was found between effect and plasma concentration. In general, the patients tolerated the planned final dose of amitriptyline well. No final dose reduction was necessary. Carbamazepine caused more side effects and the final dose had to be reduced in 4 patients. However, only 1 patient had to be taken off medication, on day 25, due to drug interaction.
The effect of imipramine on symptomatic peripheral diabetic neuropathy in 9 patients was examined in a double-blind cross-over study against placebo. The dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 300–750 nM.
Imipramine had a clear benificial effect on the symptoms of the neuropathy, whereas no changes in a range of neurophysiological measurements was detected.
Despite some adverse effects, especially of an anticholinergic nature, the patients generally preferred imipramine to placebo.
Serotoninergic pathways are believed to be important in pain mechanisms. Accordingly, we studied the action of zimelidine, a very highly serotoninergic antidepressant, in relieving the pain of post-herpetic neuralgia. Fifteen patients received zimelidine and amitriptyline in that order in an open-label cross-over study. Only one patient with zimelidine obtained a good result, whereas 8 patients on amitriptyline amitriptyline has a pain-relieving action, at least in post-herpetic neuralgia, which is not primarily linked with its serotoninergic effects and which is also independent of its effects on depression.
To study the effects of amitriptyline in treating postherpetic neuralgia, 24 patients were randomly assigned to either drug or placebo in a double-blind crossover study. We found good to excellent pain relief in 16 of 24 patients (p less than or equal to 0.001). We did not find an antidepressant effect in most patients (p greater than 0.05). The median dose of amitriptyline was 75 mg. The median blood level was 65 ng per milliliter, and of nortriptyline 30 ng per milliliter. Good responses were maintained in 12 of 22 patients. Amitriptyline is useful in treating postherpetic neuralgia and may not act as an antidepressant.
Doxepin (DOX) and desmethyldoxepin (DMD) kinetics were examined in seven depressed patients receiving single daily doses of 150 mg DOX for 1 to 3 wk. Blood samples were collected at 0, 4, 12, 15, 18, and 24 hr after the first dose, at bedtime before doses 7, 14, and 21, and at 4, 12, 15, 18, and 24 hr after the last dose. Plasma concentrations of DOX and DMD were analyzed by high-pressure liquid chromatography. Clinical response to DOX treatment was evaluated by the Zung self-rating depression scale and the Hamilton rating scale for depression. Mean DOX t1/2 after the first dose was 17.7 hr, and it rose to 21.8 hr after the last dose. Mean DMD t1/2 was not significantly affected by multiple dosing (34.2 hr after first dose and 37.1 hr after last dose). Mean values for plasma clearance, volume of distribution, and first-pass metabolism were 0.87 l/hr/kg, 23.8 l/kg, and 69.5%. In depressed patients kinetics were in the normal range. Steady-state concentrations of DOX and DMD were reached within 2 wk of beginning DOX dosing. The concentration-response curve indicated strong correlation between total DOX concentration (DOX + DMD) and antidepressant effect (r2 = 0.76).
The objective of this study was to review the effectiveness and safety of antidepressants in neuropathic pain. In a systematic review of randomised controlled trials, the main outcomes were global judgements, pain relief or fall in pain intensity which approximated to more than 50% pain relief, and information about minor and major adverse effects. Dichotomous data for effectiveness and adverse effects were analysed using odds ratio and number needed-to-treat (NNT) methods. Twenty-one placebo-controlled treatments in 17 randomised controlled trials were included, involving 10 antidepressants. In six of 13 diabetic neuropathy studies the odds ratios showed significant benefit compared with placebo. The combined odds ratio was 3.6 (95% CI 2.5-5.2), with a NNT for benefit of 3 (2.4-4). In two of three postherpetic neuralgia studies the odds ratios showed significant benefit, and the combined odds ratio was 6.8 (3.5-14.3), with a NNT of 2.3 (1.7-3.3). In two atypical facial pain studies the combined odds ratio for benefit was 4.1 (2.3-7.5), with a NNT of 2.8 (2-4.7). Only one of three central pain studies had analysable dichotomous data. The NNT point estimate was 1.7. Comparisons of tricyclic antidepressants did not show any significant difference between them; they were significantly more effective than benzodiazepines in the three comparisons available. Paroxetine and mianserin were less effective than imipramine. For 11 of the 21 placebo-controlled treatments there was dichotomous information on minor adverse effects; combining across pain syndromes the NNT for minor (noted in published report) adverse effects was 3.7 (2.9-5.2). Information on major (drug-related study withdrawal) adverse effects was available from 19 reports; combining across pain syndromes the NNT for major adverse effects was 22 (13.5-58). Antidepressants are effective in relieving neuropathic pain. Compared with placebo, of 100 patients with neuropathic pain who are given antidepressants, 30 will obtain more than 50% pain relief, 30 will have minor adverse reactions and four will have to stop treatment because of major adverse effects. With very similar results for anticonvulsants it is still unclear which drug class should be first choice. Treatment would be improved if we could harness the dramatic improvement seen on placebo in some of the trials.
Amitriptyline, but not lorazepam, relieves post herpetic neuralgia
- M B Max
- S C Schafer
- M Culnane
- B Smoller
- R Dubner
- R H Gracely