Marco Pappagallo

Opioids versus antidepressants in postherpetic neuralgia A randomized, placebo-controlled trial

Background Tricyclic antidepressants (TCA) provide less than satisfactory pain relief for postherpetic neuralgia (PHN), and the role of opioids is controversial. Objective To compare the analgesic and cognitive effects of opioids with those of TCA and placebo in the treatment of PHN. Methods Seventy-six patients with PHN were randomized in a double-blind, placebo-controlled, crossover trial. Each subject was scheduled to undergo three treatment periods (opioid, TCA, and placebo), approximately 8 weeks’ duration each. Doses were titrated to maximal relief or intolerable side effects. The primary outcome measures were pain intensity (0 to 10 scale), pain relief (0 to 100%), and cognitive function. Analyses included patients who provided any pain ratings after having received at least a single dose of a study medication. Results Fifty patients completed two periods, and 44 patients completed all three. Mean daily maintenance doses were morphine 91 mg or methadone 15 mg and nortriptyline 89 mg or desipramine 63 mg. Opioids and TCA reduced pain (1.9 and 1.4) more than placebo (0.2;p < 0.001), with no appreciable effect on any cognitive measure. The trend favoring opioids over TCA fell short of significance (p = 0.06), and reduction in pain with opioids did not correlate with that following TCA. Treatment with opioids and TCA resulted in greater pain relief (38 and 32%) compared with placebo (11%;p < 0.001). More patients completing all three treatments preferred opioids (54%) than TCA (30%;p = 0.02). Conclusions Opioids effectively treat PHN without impairing cognition. Opioids and TCA act via independent mechanisms and with varied individual effect.

Incidence, prevalence, and management of opioid bowel dysfunction.

Opioid bowel dysfunction (OBD) is a common adverse effect associated with opioid therapy. OBD is commonly described as constipation; however, it is a constellation of adverse gastrointestinal (GI) effects, which also includes abdominal cramping, bloating, and gastroesophageal reflux. The mechanism for these effects is mediated primarily by stimulation of opioid receptors in the GI tract. In patients with pain, uncontrolled symptoms of OBD can add to their discomfort and may serve as a barrier to effective pain management, limiting therapy, or prompting discontinuation. Patients with cancer may have disease-related constipation, which is usually worsened by opioid therapy. However, OBD is not limited to cancer patients. A recent survey of patients taking opioid therapy for pain of noncancer origin found that approximately 40% of patients experienced constipation related to opioid therapy (<3 complete bowel movements per week) compared with 7.6% in a control group. Of subjects who required laxative therapy, only 46% of opioid-treated patients (control subjects, 84%) reported achieving the desired treatment results >50% of the time. Laxatives prescribed prophylactically and throughout opioid therapy may improve bowel movements in many patients. Nevertheless, a substantial number of patients will not obtain adequate relief of OBD because of its refractory nature. Naloxone and other tertiary opioid receptor antagonists effectively reduce the symptoms of constipation in opioid-treated patients. However, because they also act centrally, they may provoke opioid withdrawal symptoms or reverse analgesia in some patients. There are 2 peripherally selective opioid receptor antagonists, methylnaltrexone and ADL 8-2698 (Adolor Corporation, Exton, PA, USA), that are currently under investigation for their use in treating OBD. Early studies confirm that they are effective at normalizing bowel function in opioid-treated patients without entering the central nervous system and affecting analgesia. With a better understanding of the prevalence of OBD and its pathophysiology, a more aggressive approach to preventing and treating OBD is possible and will likely improve the quality of life of patients with pain.

Capsaicin (trpv1 Agonist) Therapy for Pain Relief: Farewell or Revival?

ObjectiveIn this review, we explain our current understanding of the molecular basis for pain relief by capsaicin and other transient receptor potential vanilloid subfamily, member 1 (TRPV1) agonists. We summarize disease-related changes in TRPV1 expression and its implications for therapy and potential adverse effects. Last, we provide an overview of the current clinical uses of topical and injectable TRPV1 agonist preparations in both oncologic and nononcologic populations. MethodSearch of MEDLINE and other databases. ResultsThe capsaicin receptor TRPV1 is a polymodal nociceptor exhibiting a dynamic threshold of activation that could be lowered under inflammatory conditions. Consistent with this model, TRPV1 knock-out mice are devoid of post-inflammatory thermal hyperalgesia. TRPV1 desensitization of primary sensory neurons is a powerful approach to relieve symptoms of nociceptive behavior in animal models of chronic pain. However, over-the-counter capsaicin creams have shown moderate to poor analgesic efficacy. This is in part related to low dose, poor skin absorption, and compliance factors. Recently developed site-specific capsaicin therapy with high-dose patches and injectable preparations seem to be safe and reportedly provide long-lasting analgesia with rapid onset. ConclusionsWe argue that TRPV1 agonists and antagonists are not mutually exclusive but rather complimentary pharmacologic approaches for pain relief and we predict a “revival” for capsaicin and other TRPV1 agonists in the clinical management of pain associated with inflammation, metabolic imbalances (eg, diabetes), infections (HIV), and cancer, despite the current focus of the pharmaceutical industry on TRPV1 antagonists.

Treatment of Intractable Pain with Topical Large-dose Capsaicin: Preliminary Report

Complex regional pain syndromes (CRPS) and neuropathic pain are often poorly controlled by conventional pharmacologic interventions.We administered 8-methyl-N-vanillyl-6-noneamide (capsaicin) at doses of 5%-10% to individuals with such disorders in this trial. Previous limitations to trials with larger-dose, topical concentrations of capsaicin included intense burning sensations experienced after application. To enable patients to tolerate the high concentrations, we first performed regional anesthesia. All patients reported at least some relief. Of 10 patients, 9 obtained substantial analgesia that lasted 1-18 wk. At Week 1 after therapy, the mean verbal analog scale (VAS) scores decreased from 8.0 to 3.0. At Week 4 after therapy, mean VAS score was 4.5. Analgesia lasted from <1 wk (1 patient) to more than 50 wk (1 patient). Patients received one to eight treatments. With one exception, patients receiving more than one treatment obtained additional relief with subsequent treatment. Pain responsive to opioids was the only side effect of treatment. Large-dose capsaicin administered with regional anesthesia may effectively minimize refractory CRPS and neuropathic pain. A double-blind, placebo-controlled study in patients with bilateral peripheral neuropathy using epidural anesthesia with and without large-dose topical capsaicin is in progress. Implications: Sensory neuropathies are associated with many diseases. Pain from these disorders can produce greater disability than the primary disease processes themselves. Currently available therapies are limited. However, the intermittent application of large-dose topical capsaicin may provide significant pain relief, decrease chronic analgesic dependence, and decrease aggregate health care expenditures. (Anesth Analg 1998;86:579-83)

Outcome of Chronic Opioid Therapy for Non-Cancer Pain

Potential iatrogenic mood and cognitive declines associated with long-acting opioid therapy were examined in 19 patients receiving long-acting oral opioid medications and compared to ten patients receiving usual care. Pain, mood, and cognitive function were measured before and after achieving stable doses. In addition to reducing pain, long-acting opioid medication reduced anxiety and hostility. No declines in cognitive function were associated with the long-acting opioid medications, and the group receiving long-acting opioid medications showed significant improvement on a measure of psychomotor speed and sustained attention. Both patient groups reported significant reductions in perceived impairment in daily activities due to pain. Treatment responders taking long-acting opioid medications (63%) were taking a significantly lower dose at follow-up than the treatment non-responder group. These findings suggest that long-acting opioid medications can improve mood and do not impair cognitive functioning in patients with chronic non-cancer pain.

Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms

Background: Postherpetic neuralgia (PHN) is considered by some investigators to be predominantly a deafferentation-type central pain syndrome; others suggest that activity of remaining peripheral nociceptors plays a critical role. The authors investigated the sensory dysfunction in subjects with PHN of varying duration and at different sites to gain further insight into the mechanisms responsible for the clinical features of neuropathic pain. In addition, the relationships between ongoing pain and pain evoked by mechanical and thermal stimuli were compared in patients with trigeminal and truncal PHN, to determine if the pathophysiologic mechanisms differed among subjects. Methods : In 63 subjects with PHN, quantitative sensory testing was performed in the region of maximum allodynia or ongoing pain and the corresponding contralateral site. The intensity of ongoing pain was recorded. Sensory thresholds for warmth, coolness, heat pain, and cold pain were determined. Pain induced by various mechanical stimuli (dynamic, static, punctate) was rated using a numerical rating scale of 0-10. Results: The mean rating of ongoing PHN pain was 7.3 ± 2.0 (mean ± SD). Allodynia induced by one or more mechanical stimuli was observed in 78% of subjects. A smaller subset (40%) had hyperalgesia to heat or cold stimuli. In subjects with duration of PHN of ≤ 1 yr duration, but not in those with duration of > 1 yr, the intensity of ongoing pain correlated with intensity of allodynia induced by dynamic stimuli. Deficits in thresholds for heat and cold pain were observed in the affected region of subjects with PHN in the thoracic dermatomes (P < 0.005), but not in the trigeminal distribution. No relationship was observed between the thermal deficits and ongoing pain or mechanical allodynia in the groups of subjects with either trigeminal or thoracic PHN. conclusion: Despite a common cause, the patterns of sensory abnormalities differ between subjects. Particular differences were noted between groups with facial or truncal PHN and between groups with recent or more chronic PHN. The observations suggest that the relative contributions of peripheral and central mechanisms to the pathophysiology of pain differ among subjects and may vary over the course of PHN.

Pain coping strategies play a role in the persistence of pain in post-herpetic neuralgia.

&NA; Post‐herpetic neuralgia (PHN) is a neuropathic pain state that is often difficult to treat. Although frequently discussed in the clinical literature, little is known about the impact of pain on daily function and the extent to which psychosocial factors, in particular pain coping strategies, influence adaptation to this chronic illness. In the context of a crossover pharmacological trial, 68 patients with PHN completed a battery of psychological measures during a first drug‐free baseline period. Following discontinuation of approximately 8 weeks of treatment, 49 of these patients completed data collection during a second drug‐free assessment prior to beginning a second drug phase. Twice‐weekly telephone pain ratings were combined with questionnaire measures of perceived interference due to pain, overall activity level, depressive symptoms, and pain coping strategies. Cross‐sectional hierarchical regression analyses indicated that catastrophizing correlated with depressive symptoms but not pain, and coping self‐statements were correlated with higher levels of overall activity. Prospective hierarchical regression analyses indicated that catastrophizing at baseline predicted level of pain 8 weeks later, an effect that was independent of baseline pain and depressive symptoms. Patients who reported increasing their activity in response to pain also reported more perceived interference due to pain 8 weeks later. Higher levels of ignoring pain sensations at baseline were prospectively correlated with more depressive symptoms 8 weeks later. These findings support a role for the continued investigation of cognitive‐behavioral factors affecting the adaptation of elderly individuals experiencing PHN.

Newer antiepileptic drugs: Possible uses in the treatment of neuropathic pain and migraine

BACKGROUND Both neuropathic pain and migraine are now being treated with a variety of newer antiepileptic drugs (AEDs). The proven efficacy of gabapentin in postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), and of divalproex sodium in the prevention of migraine has led to increased clinical investigation of the newer AEDs for these conditions. While basic and clinical research are expanding the knowledge base concerning the fundamental mechanisms of neuropathic pain and migraine, growing recognition of the similarities in the pathophysiology of epilepsy, migraine, and various chronic pain disorders has further heightened interest in exploring the newer AEDs in the treatment of these conditions. OBJECTIVE The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and migraine; summarize available clinical research on the use of 5 newer AEDs (gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide) in these conditions; and provide a summary comparison of the dosing, tolerability, and drug-interaction potential of these agents. METHODS Relevant English-language articles were identified through searches of MEDLINE (1990-March 2003), American Academy of Neurology abstracts (1999-2003), and American Epilepsy Society abstracts (2000-2002). The search terms were antiepileptic medication or drug, migraine headache, neuropathic pain, pathophysiology, treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide. CONCLUSIONS The newer AEDs possess the potential advantages of better tolerability and fewer drug-drug interactions compared with standard treatments such as tricyclic antidepressants or established AEDs. However, with the exception of data supporting the efficacy of gabapentin in PHS and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal or superior efficacy relative to proven pharmacotherapies.

Analgesic effect of bamiphylline on pain induced by intradermal injection of adenosine

&NA; Adenosine is known to cause pain when injected intravenously or intra‐arterially. We have conducted a double‐blind placebo‐controlled study by injecting adenosine intradermally in 6 healthy subjects (5 male, 1 female; age: 27–34 years). Pain was assessed using the visual analogue scale. The intradermal injection of 2 &mgr;mol of adenosine produced pain significantly greater than normal saline after 15 sec (T0) (29 ± 13 vs. 7 ± 6 mm, P = 0.004), 1 min after T0 (13 ± 9 vs. 0 ± 0 mm, P = 0.002) and 2 min after T0 (4.5 ± 5 vs. 0 ± 0 mm, P < 0.05). There was evidence of hyperalgesia to mechanical and heat stimuli at the injection site (primary hyperalgesia). There was no evidence of mechanical hyperalgesia in the cutaneous area surrounding the injected site (secondary hyperalgesia). In all cases the intradermal injection of adenosine produced local hyperemia (mean surface are: 147 ± 69 mm2) which was absent after placebo injection. The pre‐injection of bamiphylline, a rather selective antagonist of A1 adenosine receptors, differently from placebo, completely suppressed the adenosine‐induced pain after 15 sec (T0) (15 ± 10 vs. 0 ± 0 mm, P = 0.002) and 1 min after T0 (9 ± 7 vs. 0 ± 0 mm, P = 0.002). No anesthesia to heat, cold and mechanical stimuli was detected at the bamiphylline site. The adenosine‐induced erythematous area was wider at the bamiphylline pre‐injected site than at the placebo pre‐injected site (173 ± 114 vs. 119 ± 85 mm2). We conclude that adenosine is an algogenic substance able to activate not only visceral but also cutaneous nociceptors. Furthermore our results suggest that the activation of nociceptors is at least partially mediated by A1 adenosine receptors.

Epidemiology, Pathophysiology, and Management of Complex Regional Pain Syndrome

Abstract: Complex regional pain syndromes (CRPS) are challenging neuropathic pain states quite difficult to comprehend and treat. Although not yet fully understood, advances are being made in the knowledge of the mechanisms involved with CRPS. Patients often present with incapacitating pain and loss of function. Patients suffering from these disorders need to have treatment plans tailored to their individual problems. A comprehensive diagnostic evaluation and early and aggressive therapeutic interventions are imperative. The therapeutic approach often calls for a combination of treatments. Medications such as antiepileptics, opioids, antidepressants, and topical agents along with a rehabilitation medicine program can help a major portion of patients suffering from these disorders. Implantable devices can aid those patients with CRPS. While progress is being made in treating patients with CRPS, it is important to remember that the goals of care are always to: 1) perform a comprehensive diagnostic evaluation, 2) be prompt and aggressive in treatment interventions, 3) assess and reassess the patients clinical and psychological status, 4) be consistently supportive, and 5) strive for the maximal amount of pain relief and functional improvement. In this review article, the current knowledge of the epidemiology, pathophysiology, diagnostic, and treatment methodologies of CRPS are discussed to provide the pain practitioner with essential and up‐to‐date guidelines for the management of CRPS.