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Thousands of individuals die each year from opioid-related overdoses. While naloxone (Narcan®) is currently the most widely employed treatment to reverse opioid toxicity, high or repeated doses of this antidote often lead to precipitated opioid withdrawal (POW). We hypothesized that a slow linear release of naloxone from a nanoparticle would induce fewer POW symptoms compared to high-dose free naloxone. First, we measured the acute impact of covalent naloxone nanoparticles (Nal-cNPs) on morphine-induced antinociception in the hotplate test. We found that Nal-cNP treatment blocked the antinociceptive effect of morphine within 15 min of administration. Next, we tested the impact of Nal-cNPs on POW symptoms in male morphine-dependent mice. To induce morphine dependence, mice were treated with 5 mg/kg morphine (or saline) twice-daily for six consecutive days. On day 7 mice received 5 mg/kg morphine (or saline) injections 2 hr prior to receiving treatment of either unmodified free naloxone, a high or low dose of Nal-cNP, empty nanoparticle (cNP-empty), or saline. Behavior was analyzed for 0-6 hr followed by 24 and 48 hr time points after treatment. As expected, free naloxone induced a significant increase in POW behavior in morphine-dependent mice compared to saline-treated mice upon free naloxone administration. In comparison, reduced POW behavior was observed with both doses of Nal-cNP. Side effects of Nal-cNP on locomotion and fecal boli production were measured and no significant side-effects were observed. Overall, our data show that sustained release of naloxone from a covalent nanoparticle does not induce severe POW symptoms in morphine-dependent mice.
Learn More >The human immunodeficiency virus (HIV) remains a major burden to the health care system and neuropathic pain is the most common neurological complication of HIV infection. Since current treatment strategies often lack satisfying pain relief, cannabinoids are discussed as a new option. We investigated cannabidivarin as treatment for HIV-associated neuropathic pain. We conducted a randomized, double-blind, placebo-controlled cross-over study. Patients underwent two successive treatment phases (4 weeks each) and were treated with cannabidivarin (400mg/d) or placebo in a randomized order. A 3-week wash-out phase was designed to eliminate potential carry-over effects. Patients were followed up for 3 weeks after the end of the second treatment phase. The primary endpoint was pain intensity on an 11-point numeric rating scale, recorded in a diary. Secondary endpoints were additional pain medication, pain characteristics and quality of life. We included 32 patients. The mean pain intensity under cannabidivarin was 0.62 points higher compared to placebo (p=0.16; 95% CI -0.27 to 1.51). Cannabidivarin did not influence the amount of additional pain medication, pain characteristics or quality of life. The incidence of adverse events was similar during both treatments. No suspected unexpected adverse reactions occurred during either treatment. Cannabidivarin was safe but failed to reduce neuropathic pain in HIV-patients. This may be explained by a lack of cannabinoid receptor activation, as indicated by preclinical experiments. Although a larger patient number might be desirable, we would not expect a change in the conclusions since the present differences are far from statistical significance. Therefore, we would currently not consider CBDV as a clinically meaningful treatment option for neuropathic pain.
Learn More >Given the ubiquitous nature of opioids in the treatment of pain, it is an interesting paradox that this class of medications also represents one of the least understood components of clinical pain medicine. For many years, there has been intense interest in the mechanisms of opioid activity, but this has not resulted in a corresponding increase in convincing clinical data. This review focuses primarily on the evidence surrounding the long-term use of opioids in chronic pain, but discussions of this research are often conflated with the very different data governing acute and cancer-related pain, where evidence of efficacy is clearer. It is therefore important to clarify the evidence-based indications for opioid therapy. There remains very little evidence that opioids improve function or quality of life beyond 3 months in people with chronic pain conditions. In all three patient populations, the development of tolerance, dependence, hyperalgesia and withdrawal are key phenomena that affect the patient experience, and in particular the decision to remain on opioids in the long term. This is a common thread that connects the opioid literature in all of these spheres, and justifies the burgeoning interest in these phenomena in the basic science literature. There is an urgent need to address these negative consequences of opioid use, in order to maximize the therapeutic benefit that opioids can offer.
Learn More >Non-steroidal anti-inflammatory drugs, cyclo-oxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of a nitric oxide donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen and ibuprofen. Administration of indomethacin (5 mgkg), ibuprofen (30 mgkg) or naproxen (30 mgkg) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. In contrast, only indomethacin was able to inhibit nitric oxide-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate nitric oxide-related signaling as a potential therapeutic approach to these disorders.
Learn More >Decreased dopaminergic activity and increased kappa opioid activity in the mesolimbic system underlie the negative emotional states related to chronic pain. However, it is not known whether these changes are just consequence of chronic pain or contribute to the sensorial changes associated with chronic pain. In this study, we asked whether the mesolimbic dopamine and kappa opioid systems contribute to the development and maintenance of chronic hyperalgesia, one of the most common sensorial changes related to chronic pain. The lesion of the dopaminergic cells of the ventral tegmental area prevented the transition from acute to chronic hyperalgesia when performed in pain-free rats, but did not affect the maintenance of chronic hyperalgesia, when performed in chronic pain in rats. As hyperalgesia becomes chronic, the dopamine levels in the nucleus accumbens decrease. The blockade of the kappa opioid receptors in the nucleus accumbens both prevented and reversed the development of chronic hyperalgesia, but did not affect its maintenance. Complementarily, the pharmacological activation of the kappa opioid receptors in the nucleus accumbens facilitated the transition from acute to chronic hyperalgesia. None of these interventions affected acute hyperalgesia. These findings suggest that the mesolimbic dopamine and kappa opioid systems specifically drive the pain chronification process, without affecting acute pain or the maintenance of chronic pain.
Learn More >Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABA) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the -terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.
Learn More >Fibromyalgia is a common and challenging chronic pain disorder with few, if any, highly effective and well tolerated treatments. Alpha-lipoic acid (ALA) is a non-sedating antioxidant with evidence of efficacy in the treatment of symptomatic diabetic neuropathy that has not been evaluated in the setting of fibromyalgia treatment. Thus, we conducted a single-centre, proof-of-concept, randomized, placebo-controlled, crossover trial of ALA for the treatment of fibromyalgia. Twenty-seven participants were recruited and 24 participants completed both treatment periods of the trial. The median maximal tolerated dose of ALA in this trial was 1,663 mg/day. Treatment-emergent adverse events with ALA were infrequent and not statistically different from placebo. For the primary outcome of pain intensity, and for several other validated secondary outcomes, there were no statistically significant differences between placebo and ALA. A post hoc exploratory subgroup analysis showed a significant interaction between gender and treatment with a significant favourable placebo-ALA difference in pain for males, but not for females. Overall, the results of this trial do not provide any evidence to suggest promise for ALA as an effective treatment for fibromyalgia, which is predominantly prevalent in females. This negative clinical trial represents an important step in a collective strategy to identify new, better tolerated and more effective treatments for fibromyalgia.
Learn More >Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn α2/α3GABAARs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain. Here, we investigated the effects of the α2/α3GABAAR subtype-selective modulator TPA023B on the tonic aversive component of pain in mice with peripheral inflammation or neuropathy. In neuropathic mice with a chronic constriction injury of the sciatic nerve, TPA023B not only reversed hyperalgesia to tactile and heat stimuli, but was also highly effective in the conditioned place preference test. In the formalin test, TPA023B not only reduced licking of the injected paw but also reversed facial pain expression scores in the mouse grimace scale assay. Taken together, our results demonstrate that α2/α3GABAA receptor subtype-selective modulators not only reduce nociceptive withdrawal responses but also alleviate the tonic aversive components of chronic pain.
Learn More >Pain after total knee arthroplasty (TKA) is a prevalent condition. This study compared the effectiveness of tapentadol extended release (ER) 50 mg x 2, oxycodone controlled release (CR) 10 mg x 2 and placebo; as added to a multimodal analgesic regime both in-hospital and at home the first week after TKA. The study was randomized and blinded for investigators, staff, outcome assessors and patients. Follow-up included pain intensity on mobilization, pain at rest, worst pain in the previous 24 hours, and adverse effects measured on 0-10 numeric rate scales. A total of 134 patients in three study groups received their allocated intervention and were included in the analysis. The primary outcome pain on mobilization the 7 first postoperative days reported as mean pain Area Under the Curve (AUC) was 528.1 (SD 267.5, IQR 356.6 to 665.4) for placebo, 427.2 (SD 203.9, IQR 303.6 to 544.3) for tapentadol ER and 507.9 (SD 243.7, IQR 292.4 to 686.8) for oxycodone CR (p=0.12). With the exception of constipation being less prevalent in the tapentadol ER group (p=0.02), we found no significant differences between treatment groups for the secondary outcomes. Tapentadol ER as an add-on to multimodal analgesia did not significantly improve pain relief when compared to oxycodone CR or placebo. Constipation was lowest in the tapentadol ER group.
Learn More >Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid, is not yet known. Ketamine, an NMDA receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone.
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