J. David Clark

Opioid-induced Hyperalgesia: A Qualitative Systematic Review

Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.

Chronic Pain Prevalence and Analgesic Prescribing in a General Medical Population

In order to better understand the prevalence of chronic pain and the frequency of analgesic use in the U.S. veteran general medical population, a review of 300 randomly selected charts was conducted. This review revealed that 50% of patients suffered from at least one type of chronic pain. A review of the corresponding pharmacy records indicated that approximately 75% of patients with chronic pain were prescribed at least 1 analgesic, and most received 2 or more. While nonsteroidal anti-inflammatory drugs were the most commonly prescribed class of analgesics, 44% of those receiving an analgesic received opioids. Examination of clinic notes revealed that the prescribing physicians documented physical examination infrequently, and commented on a specific opioid treatment plan or follow-up of that plan in a minority of cases. It appears that chronic pain is common among U.S. veterans, and that analgesics, including opioids, are commonly prescribed. Documentation of the efficacy of opioids for treating chronic pain is often scant.

Peripheral mechanisms of pain and analgesia

This review summarizes recent findings on peripheral mechanisms underlying the generation and inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generator of noxious impulses traveling towards relay stations in the spinal cord and the brain. Thus, if one finds ways to inhibit the sensitization and/or excitation of peripheral sensory neurons, subsequent central events such as wind-up, sensitization and plasticity may be prevented. Most importantly, if agents are found that selectively modulate primary afferent function and do not cross the blood-brain-barrier, centrally mediated untoward side effects of conventional analgesics (e.g. opioids, anticonvulsants) may be avoided. This article begins with the peripheral actions of opioids, turns to a discussion of the effects of adrenergic co-adjuvants, and then moves on to a discussion of pro-inflammatory mechanisms focusing on TRP channels and nerve growth factor, their signaling pathways and arising therapeutic perspectives.

Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules : A potential model of autism spectrum disorder

OBJECTIVE GABA(A) receptors play an important regulatory role in the developmental events leading to the formation of complex neuronal networks and to the behaviors they govern. The primary aim of this study was to assess whether gabrb3 gene deficient (gabrb3(-/-)) mice exhibit abnormal social behavior, a core deficit associated with autism spectrum disorder. METHODS Social and exploratory behaviors along with non-selective attention were assessed in gabrb3(-/-), littermates (gabrb3(+/+)) and progenitor strains, C57BL/6J and 129/SvJ. In addition, semi-quantitative assessments of the size of cerebellar vermal lobules were performed on gabrb3(+/+) and gabrb3(-/-) mice. RESULTS Relative to controls, gabrb3(-/-) mice exhibited significant deficits in activities related to social behavior including sociability, social novelty and nesting. In addition, gabrb3(-/-) mice also exhibited differences in exploratory behavior compared to controls, as well as reductions in the frequency and duration of rearing episodes, suggested as being an index of non-selective attention. Gabrb3(-/-) mice also displayed significant hypoplasia of the cerebellar vermis compared to gabrb3(+/+) mice. CONCLUSIONS The observed behavioral deficits, especially regarding social behaviors, strengthens the face validity of the gabrb3 gene deficient mouse as being a model of autism spectrum disorder.

Management of perioperative pain in patients chronically consuming opioids

Background The prevalence of licit and illicit opioid use is growing, and a greater percentage of chronically opioid-consuming patients are presenting for surgery. These patients can be expected to experience increased postoperative pain, greater postoperative opioid consumption, and prolonged use of healthcare resources for managing their pain. Methods Achieving adequate pain control in these patients can be challenging because commonly used strategies for alleviating postoperative pain may have diminished effectiveness. We explore the prevalence and characteristics of opioid use in the United States and discuss its impact on the perioperative management of pain. We examine mechanistically why adequate perioperative pain control in chronically opioid-consuming patients may be difficult. Conclusions We present strategies for providing adequate analgesia to these patients that include the optimal use of opioids, adjuvant medications, and regional anesthetic techniques.

A murine model of opioid-induced hyperalgesia

Controversies surround the possible long-term physiological and psychological consequences of opioid use. Analgesic tolerance and addiction are commonly at the center of these controversies, but other concerns exist as well. A growing body of evidence suggests that hyperalgesia caused by the chronic administration of opioids can occur in laboratory animals and in humans. In these studies we describe a murine model of opioid-induced hyperalgesia (OIH). After the treatment of mice for 6 days with implanted morphine pellets followed by their removal, both thermal hyperalgesia and mechanical allodynia were documented. Additional experiments demonstrated that prior morphine treatment also increased formalin-induced licking behavior. These effects were intensified by intermittent abstinence accomplished through administration of naloxone during morphine treatment. Experiments designed to determine if the mu-opioid receptor mediated OLH in our model revealed that the relatively-selective mu-opioid receptor agonist fentanyl induced the thermal hyperalgesia and mechanical allodynia characteristic of OIH when administered in intermittent boluses over 6 days. In complimentary experiments we found that CXBK mice which have reduced mu-opioid receptor binding displayed no significant OIH after morphine treatment. Finally, we explored the pharmacological sensitivities of OIH. We found that the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) and the heme oxygenase (HO) inhibitor tin protoporphyrin (Sn-P) dose-dependently reduced OIH in this model while the NSAID indomethacin had no effect. Thus we have characterized a murine model of OIH which will be useful in the pursuit of the molecular mechanisms underlying this phenomenon.

Opioid-Induced Hyperalgesia and Incisional Pain

Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg · kg−1 · day−1 for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg · kg−1 · day−1 for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds.

Isoflurane and Nociception: Spinal α2A Adrenoceptors Mediate Antinociception while Supraspinal α1 Adrenoceptors Mediate Pronociception

Background The authors recently established that the analgesic actions of the inhalation anesthetic nitrous oxide were mediated by noradrenergic bulbospinal neurons and spinal &agr;2B adrenoceptors. They now determined whether noradrenergic brainstem nuclei and descending spinal pathways are responsible for the antinociceptive actions of the inhalation anesthetic isoflurane, and which &agr; adrenoceptors mediate this effect. Methods After selective lesioning of noradrenergic nuclei by intracerebroventricular application of the mitochondrial toxin saporin coupled to the antibody directed against dopamine &bgr; hydroxylase (D&bgr;H-saporin), the antinociceptive action of isoflurane was determined. Antagonists for the &agr;1 and &agr;2 adrenoceptors were injected at spinal and supraspinal sites in intact and spinally transected rats to identify the noradrenergic pathways mediating isoflurane antinociception. Null mice for each of the three &agr;2-adrenoceptor subtypes (&agr;2A, &agr;2B, and &agr;2C) and their wild-type cohorts were tested for their antinociceptive response to isoflurane. Results Both D&bgr;H-saporin treatment and chronic spinal transection enhanced the antinociceptive effects of isoflurane. The &agr;1-adrenoceptor antagonist prazosin also enhanced isoflurane antinociception at a supraspinal site of action. The &agr;2-adrenoceptor antagonist yohimbine inhibited isoflurane antinociception, and this effect was mediated by spinal &agr;2 adrenoceptors. Null mice for the &agr;2A-adrenoceptor subtype showed a reduced antinociceptive response to isoflurane. Conclusions The authors suggest that, at clinically effective concentrations, isoflurane can modulate nociception via three different mechanisms: (1) a pronociceptive effect requiring descending spinal pathways, brainstem noradrenergic nuclei, and supraspinal &agr;1 adrenoceptors; (2) an antinociceptive effect requiring descending noradrenergic neurons and spinal &agr;2A adrenoceptors; and (3) an antinociceptive effect mediated within the spinal cord for which no role for adrenergic mechanism has been found.

Capsaicin‐Sensitive Sensory Neurons Contribute to the Maintenance of Trabecular Bone Integrity

This investigation used capsaicin to selectively lesion unmyelinated sensory neurons in rats. Neuronal lesioning induced a loss of trabecular integrity, reduced bone mass and strength, and depleted neuropeptides in nerve and bone. These data suggest that capsaicin‐sensitive sensory nerves contribute to trabecular bone integrity.

A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II.

&NA; Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous limbs of CRPS patients. Now we demonstrate that sciatic nerve section also generates chronic hindlimb warmth, distal articular tenderness, allodynia, and periarticular osteoporosis, sequelae of nerve injury resembling those observed in CRPS. We postulated that facilitated substance P signaling may contribute to these vascular and nociceptive abnormalities and attempted to reverse these changes with the long acting substance P receptor (NK1) antagonist LY303870. Hindpaw spontaneous extravasation was inhibited by LY303870. Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth. Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw. Collectively, these data further support the hypothesis that the sciatic nerve transection model closely resembles CRPS and that substance P contributes to the spontaneous extravasation, edema, warmth, and mechanical hyperalgesia observed in this model.