An intravenous ketamine test as a predictive response tool in opioid-exposed patients with persistent pain.
ABSTRACT Chronic pain patients who are treated with opioid therapy represent a significant challenge to medical professionals. When pain recurs in the face of a previously effective opioid regimen, treatment options include dose escalation, opioid rotation, drug holidays, and the addition of adjuvants. Some experts advocate the use of N-methyl-D-aspartate receptor (NMDA-R) antagonists to combat tolerance. Recently, the use of an intravenous (i.v.) ketamine infusion to predict the response to a dextromethorphan (DX) treatment trial has been described. In this study, 56 opioid-exposed patients with recurrent pain were treated with a low-dose (0.1mg/kg) i.v. ketamine test followed by a DX treatment course. Using previously designated cutoff values for a positive response to ketamine (67% or more pain relief) and DX (50% or more pain relief), the sensitivity, specificity, positive predictive value, and negative predictive value for an i.v. ketamine infusion to predict subsequent response to DX treatment were 72%, 68%, 52%, and 85%, respectively. The observed agreement between analgesic responses was 78%, indicating a highly significant correlation (r=0.54, P=0.0001). Subgroup classification revealed no significant differences in the response to either ketamine or DX treatment based on pain classification (i.e., nociceptive, neuropathic, or mixed) or placebo response. In contrast, a weaker correlation between ketamine and DX response was found in subjects requiring high-dose rather than low-dose opioid therapy. A significant correlation also was noted between the development of side effects for the two NMDA-R antagonists. Based on these results, we conclude that an i.v. ketamine test may be a valuable tool in predicting subsequent response to DX treatment in opioid-exposed patients. with persistent pain.
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ABSTRACT: Objectives The present study challenges chronic Whiplash Associated Disorders (WAD)-subjects to a pharmacological intravenous (i.v.) test with morphine, ketamine, and active placebo (midazolam). The aim was to describe the short-term responses to drugs and the assumed heterogeneity in the patterns of responses. We related the different responder groups to the results from psychometric tests.Methods The study includes 95 patients, all with chronic WAD and referred to our departments. They answered a questionnaire including the following psychometric instruments relevant for chronic pain: Beck Depression Inventory, Coping Strategies Questionnaire, Multidimensional Pain Inventory, Life Satisfaction Checklist, SF36 and EuroQol. The subjects also went through sessions with separate infusions of morphine (0.3 mg/kg), ketamine (0.3 mg/kg) and midazolam (0.05 mg/kg). Infusion time was 30 min followed by a 2-h post-infusion assessment. Assessments were made using a Visual Analogue Scale (VAS) for pain intensity and unpleasantness and by statements of per cent pain relieved. A categorical pain rating scale was also used. A positive response was defined as ≥50% decrease of the VAS-level on two consecutive assessment points during the test sessions, anything less was a non response. The placebo responders were defined as those with a positive response to the active placebo infusion.ResultsThe tests were completed by 94 subjects and 26% of these were placebo responders. Among the placebo non responders, 47% responded to morphine, 41% to ketamine, 25% to both drugs and 37% to neither morphine nor ketamine (pain intensity assessments). Similar proportions were found in the assessments of pain unpleasantness and per cent pain relieved. Approximately one in four subjects (27%, pain intensity assessment) did not respond to any of the drugs tested. This relatively high proportion of non responders seemed to be worst cases in some aspects of the psychometric tests. Generally, this non responder group had a trend to score worse for most items in the psychometric tests with some reaching significance in a univariate analysis. This result was confirmed in a multivariate context, although the results indicated only small differences between the groups. All three substances showed significant pain relief compared to baseline on all assessment points. On most variables, morphine and ketamine were significantly more effective compared to the active placebo.Conclusions There are different subgroups among subjects with chronic WAD with variations in responses to i.v. morphine, ketamine, and midazolam (active placebo). Subjects with chronic WAD who did not respond to any of the drugs tested scored badly in some aspects of the psychometric instruments.ImplicationsThe present study confirms one aspect of the heterogeneity in the population with chronic WAD. The study does not elucidate precise pain mechanisms but taken together with other studies exploring other aspects, it stresses the importance of individualizing the assessment and treatment of subjects with chronic WAD. A common clinical experience is that depression, anxiety and maladaptive coping strategies often are obstacles for successful medical treatment of chronic pain. The present study supports this experience and emphasizes the need for assessment of psychometric variables when planning the treatment of chronic WAD.Scandinavian Journal of Pain 07/2012; 3(3):151–163.
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ABSTRACT: Despite the increasing use of opioid analgesics for chronic pain management, it is unclear whether opioid dose escalation leads to better pain relief during chronic opioid therapy. In this study, we retrospectively analyzed clinical data collected from the Massachusetts General Hospital Center for Pain Medicine over a 7-year period. We examined 1) the impact of opioid dose adjustment (increase or decrease) on clinical pain score; 2) gender and age differences in response to opioid therapy; and 3) the influence of clinical pain conditions on the opioid analgesic efficacy. A total of 109 subjects met the criteria for data collection. We found that neither opioid dose increase, nor decrease, correlated with point changes in clinical pain score in a subset of chronic pain patients over a prolonged course of opioid therapy (an average of 704 days). This lack of correlation was consistent regardless of the type of chronic pain including neuropathic, nociceptive, or mixed pain conditions. Neither gender nor age differences showed a significant influence on the clinical response to opioid therapy in these subjects. These results suggest that dose adjustment during opioid therapy may not necessarily alter long-term clinical pain score in a group of chronic pain patients and that individualized opioid therapy based on the clinical effectiveness should be considered to optimize the treatment outcome. PERSPECTIVE: The study reports a relationship, or lack thereof, between opioid dose change and clinical pain score in a group of chronic pain patients. The study also calls for further investigation into the effectiveness of opioid therapy in the management of chronic nonmalignant pain conditions.The journal of pain: official journal of the American Pain Society 02/2013; · 4.22 Impact Factor
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ABSTRACT: OBJECTIVE: To examine the hypothesis that glial activation would regulate the expression of the N-methyl-D-aspartate receptor subunit 1 (NR1) in the trigeminal subnucleus caudalis (Sp5C) after temporomandibular joint (TMJ) inflammation. METHODS: Inflammation of TMJ was produced in rats by injecting 50 μL complete Freund's adjuvant (CFA) into unilateral TMJ space. Sham control rats received incomplete Freund's adjuvant injection. Mechanical nociception in the affected and non-affected TMJ site was tested by using a digital algometer. Fractalkine, fluorocitrate, and/or MK801 were intracisternally administrated to examine the relationship between astroglial activation and NR1 upregulation. RESULTS: CFA TMJ injection resulted in persistent ipsilateral mechanical hyperalgesia 1, 3, and 5 days after CFA injection. The inflammation also induced significant upregulation of CX3C chemokine receptor 1 and glial fibrillary acidic protein (GFAP) beginning on day 1 and of NR1 beginning on day 3 within the ipsilateral Sp5C. Intracisternal administration of fluorocitrate for 5 days blocked the development of mechanical hyperalgesia as well as the upregulation of GFAP and NR1 in the Sp5C. Conversely, intracisternal injection of fractalkine for 5 days exacerbated the expression of NR1 in Sp5C and mechanical hyperalgesia induced by TMJ inflammation. Moreover, once daily intracisternal fractalkine administration for 5 days in naïve rats induced the upregulation of NR1 and mechanical hyperalgesia. CONCLUSIONS: These results suggest that astroglial activation contributes to the mechanism of TMJ pain through the regulation of NR1 expression in Sp5C.Pain Medicine 10/2012; · 2.24 Impact Factor