The 22nd Annual Scientific Meeting of the American Pain Society took place on March 20-23, 2003, in Chicago, Illinois
Source: Medscape Neurology & Neurosurgery (posted 05/29/2003) Atif B. Malik, MD(1), Zahid H. Bajwa, MD(2)
(1)Atif B. Malik, MD, Pain Fellow, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
(2)Zahid H. Bajwa, MD, Assistant Professor of Anesthesia (Neurology), Harvard Medical School, Boston, Massachusetts; Director, Education and Clinical Pain Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Traditionally, the American Pain Society's (APS) annual meeting mixes science and clinical practice in a milieu of educational workshops, with original research abstracts presented in a relatively small poster session. But as scientific and clinical advances in pain medicine expand, the amount and variety of original research presented at the annual meeting of the APS has grown in breadth and depth. The following discussion highlights key research in basic science and new treatments, as well as treatment-related complications presented in poster sessions at the 22nd Annual Scientific Meeting of the APS.
Oxycodone-Related Deaths. Oxycodone has received considerable notoriety in the media recently. In an attempt to clarify factors involved in deaths related to oxycodone abuse, Haddox and colleagues from Purdue Pharma, Stamford, Connecticut, examined the deaths using a Drug Abuse Warning Network (DAWN)-based classification system. They assembled an Oxycodone Postmortem Database comprising 1243 cases that consisted of solicited submissions from medical examiner and coroner offices in 23 states during a 29-month period ending in January 2002.
Of the 1014 evaluable cases involving oxycodone, 921 (90.8%) were found to be related to drug abuse, and 93 (9.2%) were categorized as not involving drug abuse. In total, 31 (3.4%) of the cases in which drug abuse was implicated reported oxycodone as a single entity used.
Investigators reported that 96.6% of the deaths involved multiple drugs in which there was at least 1 other possible contributory drug in addition to oxycodone. Most prevalent drug combinations were oxycodone in combination with: benzodiazepines, alcohol, cocaine, other narcotics, marijuana, or antidepressants. These findings are important from a medical-legal standpoint and as a key analysis in the field of pain medicine.
Sex Differences in Morphine Metabolism. Pain is difficult to measure during the acute postoperative period, which limits our ability to analyze these states and renders their management more challenging. Few high-quality, randomized, prospective, controlled trials have compared agents and their metabolites. Now, a study from Idaho State University, Pocatello, Idaho, by Ratka and associates has shown sex differences in pharmacokinetics of morphine glucuronides in the elderly.
Investigators administered a single oral dose of morphine (0.5 mg/kg) to elderly men and women (over 60 years) and then measured concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G). Plasma profiles of morphine did not differ significantly between men and women but the time required to reach the maximum concentration of M3G was significantly longer (1.7-fold) in women than men.
However, for the initial 2-3 hours, levels of M6G were higher in men than women. The clearance of M3G and M6G was significantly lower in women compared with men. The M3G clearance was about 2 times lower than the clearance of M6G. These investigators concluded that among the elderly, there are sex differences in the pharmacokinetics of morphine glucuronides but not morphine. The results indicate that with repeated doses of morphine, M3G may accumulate to a greater extent in elderly women than elderly men. It is hoped that, as more studies are performed, we will be able to define more clinical end points, and develop newer drugs with rapid onset and offset, no active metabolites, and reduced morbidity and mortality for our patients.
CSF Chemistry and Chronic Intrathecal Morphine. Despite widespread use of intrathecal morphine for controlling chronic cancer-related pain, no studies have examined the long-term effects of chronic intrathecal morphine infusions on CSF chemistry (protein, glucose, WBC). This is particularly important for patients who are being evaluated for possible CSF infection during chronic spinal drug delivery. Furthermore, granuloma formation on the catheter tip is a potential complication, and knowing the baseline CSF chemistry compared with subsequent measurements may help determine whether any of these substances add to the risk for granuloma formation.
Wallace and Yaksh from the University of California, San Diego, obtained CSF samples from 17 patients receiving chronic intrathecal morphine via implanted infusion pump. Samples were assayed for protein, glucose, and white and red blood cells. The investigators used fluoroscopy to check the integrity and location of the catheter tip. They found no correlation between morphine concentrations and CSF protein, glucose, WBC, or RBC levels. Likewise, they found no correlation between morphine daily dose and levels of CSF protein, glucose, WBC, or RBC. Thus, chronic intrathecal morphine infusions do not cause abnormalities in CSF protein, glucose, or red or white blood cells, and therefore are likely not a risk factor for CSF infection or granuloma formation.
Until we find markers for granuloma formation in such cases, it is probably prudent that all patients receiving long-term intrathecal analgesia undergo periodic radiographic surveillance to further define their risk for developing occult catheter-associated masses and to allow intervention before neurologic injury can develop.
NMDA Receptors and Antagonists. N-methyl-D-aspartate (NMDA) receptors in the spinal cord mediate the pain signal transmission, but also trigger some local mechanisms to regulate responses to painful stimulation. Wang and associates from Tianjin University General Hospital, Tianjin, China, examined the mechanism through which NMDA receptors upregulate nerve growth factor (NGF) expression in dorsal horn neurons during peripheral inflammatory hyperalgesia. NGF is a pain-related neural modulator that works by retrograde transport from the periphery to the spinal cord and is expressed by dorsal horn neurons.
The NGF from the periphery and spinal cord may contribute to the rise in NGF during the peripheral inflammatory hyperalgesia. If peripheral inflammation upregulates the expression of NGF in dorsal horn neurons through a NMDA receptor-mediated mechanism, then preemptive blockade of the NMDA receptor may prevent the increased NGF expression in dorsal horn neurons.
These investigators tested this mechanism by injecting MK-801, a noncompetitive antagonist of NMDA receptors, into the intrathecal space of adult rats, blocking NMDA receptors in the lumbar spinal cord before artificial peripheral inflammation was produced by cutaneous microinjection of formalin into a hind paw. They then used an oligodeoxyribonucleotide probe to measure the synthesis of NGF in the dorsal horn neurons. Results showed that mRNA of NGF was upregulated unilaterally in lumbar spinal cord dorsal horn neurons 1 day after the formalin cutaneous injection into the hind paw.
However, preemptive intrathecal MK-801 injection prevented the dorsal horn neurons from increasing the expression of NGF at 24 hours after formalin injection, and reduced pain-associated behaviors.
These findings are consistent with the hypothesis that peripheral inflammation causes NGF expression in spinal cord dorsal horn neurons through an NMDA receptor-mediated mechanism. Thus, blocking spinal cord NMDA receptors may attenuate the peripheral inflammatory pain by downregulating the NGF-related pain responses. Previous in situ hybridization experiments performed during the reinnervation process revealed an overexpression of mRNA coding for NR1 subunit of NMDA receptors in the spiral ganglion neurons, implicating these receptors in neural regenerative processes. MK-801 may play a role in pain management, but so far agents from this class have not been used extensively in clinical practice.
Intranasal Ketamine for Postoperative Pain
Postoperative pain can reduce mobility and thus impede recovery after surgery. Oral surgery is often used as a surrogate for moderate-to-severe postoperative pain.
Christensen and coworkers, under the auspices of Jean Brown Associates, clinical research consultants in Salt Lake City, Utah, reported the results of 2 dose-ranging phase 2 clinical studies to evaluate the safety and efficacy of analgesic doses of intranasal ketamine for moderate-to-severe pain in postoperative patients.
This group used 5 doses of intranasal ketamine (2.5 mg, 5 mg, 10 mg, 30 mg, or 50 mg) and placebo in 2 parallel, randomized, double-blind studies. The study population comprised a total of 80 patients undergoing removal of 2-4 impacted third molars. At the onset of moderate-to-severe postoperative pain, patients self-administered intranasal ketamine or placebo using a metered spray pump. Analgesic efficacy was assessed over a 3-hour period following drug administration.
In both studies, intranasal ketamine at doses as low as 10 mg provided a rapid onset (within 2-10 minutes of administration) of analgesia. The 50-mg dose produced a significant analgesic effect compared with placebo, with a trend toward analgesia for the 10- and 30-mg doses. Side effects were noted more frequently by patients receiving higher doses of ketamine; however, systolic and diastolic blood pressure, heart rate, and oxygen saturation remained stable; no patient suffered hallucinations. Thus, intranasal ketamine may offer a safe, nonopiate, analgesic alternative for relief of moderate-to-severe postoperative pain.
NMDA receptors are known to be involved in the pathogenesis of chronic neuropathic pain. Likewise, NMDA-receptor antagonists have proved effective in animal models of neuropathic pain. Unfortunately, longer-term treatment with most high-affinity NMDA-receptor antagonists has been associated with serious adverse effects, including memory loss. Memantine is in a class of moderate affinity noncompetitive NMDA-receptor antagonists. Because the drug selectively targets pathologic but not physiologic activation of NMDA receptors, it is well tolerated.
Banerjee, a scientist at Forest Laboratories, Inc, New York, NY, reported on the effects of memantine in several animal models of acute and chronic neuropathic pain. Memantine inhibited mechanical hyperalgesia in a dose-dependent fashion for up to 6 hours in rats with painful peripheral neuropathy induced by ligation of L5 and L6 spinal nerves. Chronic treatment with memantine at doses of 8 mg/kg/hr for 7 days produced antinociceptive effects lasting 3 days after the drug was discontinued. Memantine exhibited greater efficacy (96%) than dextromethorphan (65%), MK-801 (34%), or ketamine (18%) administered intrathecally to maximum doses that did not cause motor impairment.
In a second rat model of persistent painful mononeuropathy induced by chronic constrictive injury to the sciatic nerve, intraperitoneal memantine reduced thermal hyperalgesia both prophylactically, at doses of 3 mg/kg given for 7 days before the injury, and therapeutically, at doses of 10 mg/kg given 7 or 14 days after the injury. Finally, in a monkey model of L7-ligation-induced neuropathy, memantine administered at L6-L7 through a microdialysis probe significantly lowered the extracellular responses of spinothalamic tract cells to all cutaneous stimuli.
Pregabalin and Fibromyalgia
The pathophysiology of fibromyalgia is not well understood. However, fibromyalgia may originate through mechanisms similar to those active in painful diabetic neuropathy and postherpetic neuralgia. Clinical studies of pregabalin have found it to be effective for relieving the neuropathic pain associated with painful diabetic neuropathy and postherpetic neuralgia.
Thus, investigators hypothesize that pregabalin may also help patients with fibromyalgia. Dworkin from University of Rochester School of Medicine and Dentistry, Rochester, NY, and colleagues from several US centers and Pfizer Global Research and Development, Ann Arbor, Michigan, evaluated the efficacy and safety of pregabalin for reducing pain and symptoms associated with fibromyalgia in a randomized, double-blind, placebo-controlled, monotherapy trial. A total of 529 patients who met the American College of Rheumatology fibromyalgia criteria participated. Patients completed a 1-week baseline phase and were randomized to receive either placebo or pregabalin 150, 300, or 450 mg daily in an 8-week double-blind, fixed-dose treatment phase.
Pregabalin-treated patients at the highest dose, 450 mg/day, experienced significant improvement as evidenced in the end point mean pain score (-0.93; P = .0009) compared with those receiving placebo. Patients in this treatment dose arm were also more likely to experience a 50% reduction in pain from baseline (29% vs 13%, P = .003). In all, 48 patients (9%) withdrew because of adverse events (commonly dizziness and drowsiness) and 44 patients (8%) because of poor efficacy. Thus, in this study, 450 mg pregabalin daily relieved the pain, enhanced sleep, reduced fatigue, and improved the health-related quality of life for patients with fibromyalgia. Although these data appear exciting, fibromyalgia is a difficult disorder to treat and more research is still needed.
New Antiepileptic Drug for Neuropathic Pain
Many antiepileptic drugs are being used to treat neuropathic pain. The newest to be tested in models of neuropathic pain is ucb 34714, a pyrrolidone derivative. This drug is structurally related to the antiepileptic drug levetiracetam, which has been shown to possess anti-hyperalgesic effects in animal models of neuropathic pain. The new compound was discovered because it had an affinity for the CNS-specific levetiracetam binding site.
Lamberty and colleagues, from Clermont-Ferrand, Braine l'Alleud, Belgium, compared ucb 34714 and gabapentin in 2 animal models of neuropathic pain. In these studies, ucb 34714 did not produce an analgesic effect in acute pain reflexes but did induce an anti-hyperalgesic effect in both diabetic and mononeuropathic rats, comparing favorably with gabapentin. These data suggest that ucb 34714 is a potential new therapy for patients with neuropathic pain.
Thalidomide and Complex Regional Pain Syndrome
Thalidomide was banned from use in the 1960s when it produced severe teratogenic effects. It has lately returned to clinical practice, and in 1998, the US Food and Drug Administration (FDA) approved its use for the treatment of the debilitating and disfiguring lesions associated with erythema nodosum leprosum, a complication of Hansen's disease, commonly known as leprosy. Thalidomide has antiangiogenic and immunomodulatory properties and is an effective inhibitor of TNF-alpha in a number of malignancies.
Recently, a group from Mayo Clinic in Rochester, Minnesota, reported a patient in whom symptoms of complex regional pain syndrome (CRPS) resolved when she was treated with thalidomide for multiple myeloma. This group subsequently began a phase 2 trial of thalidomide for CRPS.
Bengtson and colleagues evaluated 12 patients with recalcitrant upper limb CRPS. Patients had suffered CRPS for at least 1 year with no relief despite extensive interventions. They were treated with a gradually progressive dose of thalidomide (100 mg daily up to 400 mg daily) during a 6-month period. Six patients dropped out of the study because of medication side effects, including constipation, somnolence, rash, and edema. Four of the 6 remaining patients reported significant reductions in pain with average initial scores of 7.2 on VAS, dropping to 3.4 by the end of the study. The other 2 patients tolerated the drug but experienced no significant improvement in pain symptoms.
This study found that thalidomide relieves pain in some patients with recalcitrant CRPS and supports the value of further study of the drug in larger, placebo-controlled studies of patients with CRPS.
Because of its potential for causing birth defects, the FDA invoked unprecedented regulatory authority to tightly control the marketing of thalidomide in the United States. A System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) oversight program has been initiated that includes limiting authorized prescribers and pharmacies, providing extensive patient education about the risks associated with thalidomide, and requiring a 100% patient registry. This oversight program is designed to help insure a zero-tolerance policy for thalidomide exposure during pregnancy.
Oxymorphone for Osteoarthritis Pain
In a double-blind, placebo-controlled study from Endo Pharmaceuticals, Chadds Ford, Pennsylvania, Kivitz and coworkers evaluated 357 patients with grade II-IV osteoarthritis (hip/knee) and pain in the index joint of at least 40 mm. Following an analgesic washout period they were randomized to receive 1 of 4 regimens:
• oxymorphone extended-release (ER) 10 mg every 12 hours for 2 weeks (n = 92);
• oxymorphone ER 20 mg every 12 hours during week 1 and 40 mg every 12 hours during week 2 (n = 91);
• oxymorphone ER 20 mg every 12 hours during week 1 and 50 mg every 12 hours during week 2 (n = 87);
• placebo (n = 87).
Patients were not allowed any rescue medications during the study period. The investigators recorded a statistically significant dose-response relationship with reductions in pain intensity. In general, patients experienced clinical improvement with the 10-mg dose but statistically significant relief at both the 40-mg and 50-mg doses.
Adverse events were most common during week 1 and did not increase with titration to higher doses. Oxymorphone ER provides another option for patients with acute, chronic, and cancer pain.
There were several posters on botulinum toxin (BTX) A and B showing both of these agents to have similar efficacy. Both agents have been used successfully for myofascial pain as well as headaches. The mechanism by which BTX works had been thought to occur at the level of the neuromuscular junction. However, newer data suggest that BTX may have an antinociceptive effect and may be involved in inhibiting peripheral and central nociceptive processing. Cui and colleagues have found histologic evidence that after subcutaneous injection of BTX in the rat formalin model, there is inhibition of the formalin-evoked c-fos expression in the superficial dorsal horn.
At the APS meeting, a group from Beth Israel Deaconess Medical Center/Harvard Medical School in Boston, Massachusetts, reported using BTX-A to successfully treat 2 patients with severe allodynia.
One of the patients was a 58-year-old man with chronic right-sided headaches for 2 years who had developed allodynia (VAS 8/10) of the ipsilateral temporal regions. He tried antiepileptic medications, opiates, antidepressants, anxiolytics, and nonsteroidal anti-inflammatory drugs (NSAIDs) without significant relief.
A trial of venlafaxine led to tinnitus, and oxcarbazepine with amitryptyline worsened his headaches. Within a week of receiving an injection of BTX-A, 100 units in 3 mL normal saline into the temporalis and frontalis muscles, he experienced 70% to 80% relief in the pressure symptoms and a reduction in headache frequency, but no change in intensity. After 1 month, 100 units of BTX-A divided into 12 injection sites bilaterally (temporal, frontal, and masseters) relieved the allodynia, although his headache improved only marginally. After 4 months, allodynia reappeared and was again relieved by BTX-A injection.
The second patient was a 65-year-old man who, 2 months after thoracotomy, developed allodynia and muscular hypertrophy around the scar. Intermittent latissimus dorsi spasm/pain and pain around the scar were both 8-9/10 on the VAS. In addition to the allodynia surrounding the scar, the latissimus was tender to touch.
Tricyclics, anticonvulsants, NSAIDs, muscle relaxants, and opioids were not helpful. Topiramate 300 mg once daily and EMLA cream provided good relief of the allodynia but not of spasms. "Trigger point" and intralesional (scar) injection of 0.25% bupivicaine and methylprednisolone 20 mg was effective for both, but short-lived. BTX-A 100 units in 10 mL normal saline was injected into 5 areas of the latissimus dorsi muscle every 12 weeks; the pain decreased by 80% and the allodynia resolved while on this regimen.
Although these results are exciting, further basic science research and clinical data are needed to substantiate the reported findings.
Medscape Neurology & Neurosurgery 5(1), 2003. © 2003 Medscape