The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial
Low-dose vaporized cannabis significantly improves neuropathic pain.
We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. ⋯ The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning.
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Persistent inflammation promotes internalization of synaptic GluR2-containing, Ca(2+)-impermeable AMPA receptors (AMPARs) and insertion of GluR1-containing, Ca(2+)-permeable AMPARs at extrasynaptic sites in dorsal horn neurons. Previously we have shown that internalization of synaptic GluR2-containing AMPARs requires activation of spinal cord protein kinase C alpha (PKCα), but molecular mechanisms that underlie altered trafficking of extrasynaptic AMPARs are unclear. Here, using antisense (AS) oligodeoxynucleotides (ODN) that specifically knock down PKCα, we found that a decrease in dorsal horn PKCα expression prevents complete Freund's adjuvant (CFA)-induced increase in functional expression of extrasynaptic Ca(2+)-permeable AMPARs in substantia gelatinosa (SG) neurons of the rat spinal cord. Augmented AMPA-induced currents and associated [Ca(2+)](i) transients were abolished, and the current rectification 1 day post-CFA was reversed. These changes were observed specifically in SG neurons characterized by intrinsic tonic firing properties, but not in those that exhibited strong adaptation. Finally, dorsal horn PKCα knockdown produced an antinociceptive effect on CFA-induced thermal and mechanical hypersensitivity during the maintenance period of inflammatory pain, indicating a role for PKCα in persistent inflammatory pain maintenance. Our results indicate that inflammation-induced trafficking of extrasynaptic Ca(2+)-permeable AMPARs in tonically firing SG neurons depends on PKCα, and that this PKCα-dependent trafficking may contribute to persistent inflammatory pain maintenance. ⋯ This study shows that PKCα knockdown blocks inflammation-induced upregulation of extrasynaptic Ca(2+)-permeable AMPARs in dorsal horn neurons and produces an antinociceptive effect during the maintenance period of inflammatory pain. These findings have potential implications for use of PKCα gene-silencing therapy to prevent and/or treat persistent inflammatory pain.
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Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic-prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic-prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic-prescribing algorithms. ⋯ Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic-prescribing algorithms that could optimize opioid analgesic effectiveness and mitigate risks of opioid-related abuse and mortality.
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Comparative Study
Comparison of opioid doctor shopping for tapentadol and oxycodone: a cohort study.
Obtaining opioids from multiple prescribers, known as doctor shopping, is 1 example of opioid abuse and diversion. The dual mechanism of action of tapentadol could make tapentadol less likely to be abused than other opioids. The aim of this retrospective cohort study was to compare the risk of shopping behavior between tapentadol immediate release (IR) and oxycodone IR. Subjects exposed to tapentadol or oxycodone with no recent opioid use were included and followed for 1 year. The primary outcome was the proportion of subjects who developed shopping behavior defined as subjects who had opioid prescriptions written by >1 prescriber with ≥1 day of overlap filled at ≥3 pharmacies. The opioids involved in the shopping episodes were assessed. A total of 112,821 subjects were exposed to oxycodone and 42,940 to tapentadol. Shopping behavior was seen in .8% of the subjects in the oxycodone group and in .2% of the subjects in the tapentadol group, for an adjusted odds ratio of 3.5 (95% confidence interval, 2.8 to 4.4). In the oxycodone group, 28.0% of the shopping events involved exclusively oxycodone, whereas in the tapentadol group, .6% of the shopping events involved exclusively tapentadol. Results suggest that the risk of shopping behavior is substantially lower with tapentadol than with oxycodone. ⋯ The risk of opioid doctor shopping, ie, obtaining opioid prescriptions from multiple prescribers, is lower with tapentadol than with oxycodone.
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Randomized Controlled Trial
Expectations modulate heterotopic noxious counter-stimulation analgesia.
The present study examined the contribution of expectations to analgesia induced by heterotopic noxious counter-stimulation (HNCS) in healthy volunteers assigned to a control group or 1 of 3 experimental groups in which expectations were either assessed (a priori expectations) or manipulated using suggestions (hyperalgesia and analgesia). Acute shock-pain, the nociceptive flexion reflex (RIII-reflex), and shock-related anxiety were measured in response to electrical stimulations of the right sural nerve in the baseline, HNCS, and recovery periods. Counter-stimulation was applied on the contralateral forearm using a flexible cold pack. A priori expectations were strongly associated with the actual magnitude of the analgesia induced by HNCS. In comparison to the control condition, suggestions of hyperalgesia led to an increase in RIII-reflex amplitude and shock-pain, while suggestions of analgesia resulted in a greater decrease in RIII-reflex amplitude, which confirms that the analgesic process normally activated by HNCS can be blocked or enhanced by the verbal induction of expectations through suggestions. Changes in shock-anxiety induced by these suggestions were correlated to changes in shock-pain and RIII-reflex, but these changes did not emerge as a mediator of the association between manipulated expectations and HNCS analgesia. Overall, the results demonstrate that HNCS analgesia is modulated by expectations, either from a priori beliefs or suggestions, and this appears to be independent of anxiety processes. ⋯ This study demonstrates that a priori and manipulated expectations can enhance or block HNSC analgesia. Results also suggest that expectations might influence responses to analgesic treatments by altering descending modulation and contribute to observed deficit in pain inhibition processes of chronic pain patients.