Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial.

OBJECTIVE: To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. METHODS: Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. RESULTS: Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. CONCLUSION: Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.

Pilot clinical trial of gabapentin to decrease postoperative delirium in older patients.

In this randomized pilot clinical trial, the authors tested the hypothesis that using gabapentin as an add-on agent in the treatment of postoperative pain reduces the occurrence of postoperative delirium. Postoperative delirium occurred in 5/12 patients (42%) who received placebo vs 0/9 patients who received gabapentin, p = 0.045. The reduction in delirium appears to be secondary to the opioid-sparing effect of gabapentin.

A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain.

BACKGROUND: Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore. OBJECTIVE: To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study. METHODS: With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study. RESULTS: There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%). CONCLUSIONS: Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.

Effect of intravenous magnesium on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers.

We investigated the effects of i.v. magnesium on secondary hyperalgesia following heat/capsaicin stimulation in human volunteers. Twenty-five volunteers were included in this double blind, randomized, crossover study. Sensitization was induced in the volunteers, who were then subjected to either i.v. saline or magnesium sulphate. No analgesic or antihyperalgesic effect could be demonstrated in sensitized skin during infusion of magnesium. In contrast, painfulness of thermal stimulation was increased in normal skin. These results suggest that i.v. magnesium has no important analgesic effects in clinically relevant doses.

Effect of systemic adenosine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers.

BACKGROUND AND OBJECTIVES: Adenosine is an endogenous compound that may have analgesic effects. Results from clinical trials are not consistent, however, and there is a need for large-scale, randomized, placebo-controlled studies to clarify the role of adenosine in the treatment of pain states, including acute nociceptive pain and pain involving central sensitization. METHODS: The analgesic and antihyperalgesic effect of systemic adenosine on the heat/capsaicin sensitization model of experimental pain was investigated in 25 healthy human volunteers. Sensitization was produced by heating the skin to 45 degrees C for 5 minutes, followed by a 30-minute application of 0.075% capsaicin cream, and maintained by periodically reheating the sensitized skin to 40 degrees C for 5 minutes at 40-minute intervals. Subjects received intravenous adenosine 60 microg/kg/min or saline for 85 minutes. Areas of secondary hyperalgesia to von Frey hair and brush stimulation, heat-pain detection thresholds (HPDTs) in normal and sensitized skin, and painfulness of stimulation with 45 degrees C for 1 minute (LTS) in normal skin were quantified before, during, and after study drug infusion. RESULTS: Systemic adenosine had no effect on the area of secondary hyperalgesia to von Frey hair or brush stimulation, HPDT in normal or sensitized skin, or painfulness of LTS in normal skin. CONCLUSION: We conclude that adenosine has no effect on acute nociceptive pain induced by heat stimulation or on secondary hyperalgesia induced by heat/capsaicin sensitization in healthy volunteers.

Effect of remifentanil on pain and secondary hyperalgesia associated with the heat--capsaicin sensitization model in healthy volunteers.

BACKGROUND: The heat--capsaicin sensitization model was developed as a noninvasive and noninjurious human experimental pain model. The sequential application of moderate intensity thermal and topical chemical stimuli produces stable and long-lasting areas of cutaneous secondary hyperalgesia. The aim of the present study was to validate the heat--capsaicin sensitization model as a tool for testing analgesic drug efficacy. Responsivity of model-associated measures was tested with remifentanil, a potent and ultrashort acting mu-opioid agonist. METHODS: Sensitization was induced by heating forearm skin with a thermode at 45 degrees C for 5 min, immediately followed by application of 0.075% capsaicin cream for 30 min. Sensitization was rekindled four times at 40-min intervals with the thermode at 40 degrees C for 5 min. After each rekindling, areas of secondary hyperalgesia were measured, and the painfulness of thermal stimulation in normal skin with 45 degrees C for 1 min (long thermal stimulation [LTS]) was rated. Before and during the second rekindling, remifentanil 0.10 microg x kg(-1) x min(-1) or saline-placebo was infused for 35 min. RESULTS: Infusion of remifentanil reduced the areas of secondary hyperalgesia to 29--30% of baseline size compared with 75--83% during placebo. Similarly, remifentanil reduced the painfulness of LTS to 29% of baseline severity compared with 84% during placebo. Areas of secondary hyperalgesia and LTS painfulness returned to baseline levels by the time of the third rekindling, demonstrating rapid disappearance of remifentanil analgesia and possibly transient spontaneous opioid withdrawal hyperalgesia. CONCLUSION: Using the heat-capsaicin sensitization model, opioid analgesia and suppression of secondary hyperalgesia was reliably demonstrated without skin injury.

Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions.

OBJECTIVE: To assess the efficacy, tolerability, and safety of riluzole in the treatment of peripheral neuropathic pain conditions. BACKGROUND: Both basic and clinical research has demonstrated that drugs with sodium channel and NMDA antagonism can be effective in alleviating neuropathic pain. Riluzole, a drug currently used for treatment of ALS, possesses these properties. It was hypothesized that riluzole would be effective in reducing the pain in subjects with peripheral neuropathic pain. METHODS: Two randomized, placebo-controlled, crossover studies were performed at two sites. Study 1 compared 100 mg/day of riluzole (the currently recommended dosage for treatment of ALS) versus placebo, and Study 2 compared 200 mg/day of riluzole versus placebo. Each treatment phase (both studies) was 2 weeks long, separated by 2-week wash-out periods. Outcome measures included change in the score on a 100-mm pain intensity visual analog scale, the Neuropathic Pain Scale, allodynia, hyperalgesia, and preference for study treatment phase. RESULTS: Twenty-two subjects completed Study 1, and 21 subjects completed Study 2. Four subjects (two from each study) discontinued the study because of intolerable side effects. No statistical difference was found for any study outcome measure between riluzole and placebo for either study. In Study 1, pain intensity was more likely to increase than decrease with riluzole (mean treatment difference 8.7 mm; 95% CI -19.5 to +2.1 mm). In Study 2, very slight pain reduction was observed with riluzole compared with placebo (mean treatment difference 1.4 mm; 95% CI -5.1 to +8.0 mm). In both studies, the majority of subjects chose "no change" in pain on the category relief scale after placebo and riluzole treatment phases. On study completion, no treatment preference was reported by 76% of the subjects in Study 1 and by 61% of the subjects in Study 2. CONCLUSIONS: Doses of riluzole at (100 mg) or above (200 mg) those used for the treatment of ALS were not effective in alleviating peripheral neuropathic pain.

The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers.

UNLABELLED: Although effective in neuropathic pain, the efficacy of systemic lidocaine in non-neuropathic pain remains uncertain. We investigated the analgesic effect of systemic lidocaine on the heat/capsaicin sensitization model of experimental pain in 24 volunteers. Sensitization was produced by heating the skin to 45 degrees C for 5 min, followed by a 30-min application of 0.075% capsaicin cream, and maintained by periodically reheating the sensitized skin. Subjects received IV lidocaine (bolus 2 mg/kg, then infusion 3 mg. kg. h), or saline for 85 min. Areas of secondary hyperalgesia, heat pain detection thresholds, and painfulness of stimulation with 45 degrees C for 1 min (long thermal stimulation) were quantified. Systemic lidocaine reduced the area of secondary hyperalgesia to brush, but not to von Frey hair stimulation. Lidocaine did not alter heat pain detection thresholds or painfulness of long thermal stimulation in normal skin. We conclude that, at infusion rates in the low- to mid-antiarrhythmic range, lidocaine has no effect on acute nociceptive pain but does have a limited and selective effect on secondary hyperalgesia. IMPLICATIONS: The efficacy of systemic lidocaine in nonneuropathic pain remains uncertain. This study investigates the effect of systemic lidocaine on experimental-induced hyperalgesia in 25 volunteers. Hyperalgesia was induced by using an experimental pain model that uses heat and capsaicin in combination. Systemic lidocaine showed a selective effect on secondary hyperalgesia.

Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.

Sports-related soft tissue injuries, such as sprains, strains, and contusions, are a common painful condition. Current treatment includes oral nonsteroidal anti-inflammatory drugs (NSAIDs), which have a high incidence of intolerable gastrointestinal side effects. Topically applied drugs have the potential to act locally in the soft tissues without systemic effects. This study assessed the efficacy and safety of topical diclofenac (NSAID) patch applied directly to the painful injury site for the treatment of acute minor sports injury pain. Adult subjects (N = 222) were recruited from two communities for a multicenter, randomized, placebo-controlled, parallel design study. All subjects had suffered a painful minor sports injury within the prior 72 hours of study entry. Either a diclofenac epolamine or placebo topical patch was applied directly to the skin overlying the painful injured site twice daily for 2 weeks. Measures of pain intensity were performed in a daily diary and at clinic visits on days 3, 7, and 14. Diclofenac patch was superior to placebo patch in relieving pain. Statistical significance was seen on clinic days 3 (P = 0.036) and 14 (P = 0. 048), as well as the daily diary pain ratings at days 3, 7, and 14 (P < or =0.044). No statistically significant differences were seen in any safety or side-effect measures with the diclofenac patch as compared to the placebo patch. Diclofenac epolamine patch is an effective and safe pain reliever for treatment of minor sports injury pain. The advantages of this novel therapy include its ease of use and lack of systemic side effects.

Will ion-channel blockers be useful for management of nonneuropathic pain?

For neuropathic pain, there is evidence that the analgesic effect of intravenous sodium-channel blockers is robust and dose dependent. Oral agents are less impressive, but efficacious nonetheless, especially at higher doses. Despite the evidence from animal studies for a role of sodium channels in inflammatory hyperalgesia, the clinical evidence of analgesic effect of oral and intravenous sodium channel blockers in both acute and chronic nonneuropathic pain is equivocal. The results to date from human experimental pain models suggest a lack of effect of systemic lidocaine on acute nociceptive pain and that the effect on cutaneous hyperalgesia is modest, at best. Furthermore, the literature suggests that the systemic lidocaine analgesia is both dose and diagnosis dependent.

Quantitation of levorphanol in human plasma at subnanogram per milliliter levels using capillary gas chromatography with electron-capture detection.

A gas chromatographic method for the determination of levorphanol in human plasma is described. The method utilizes extractive alkylation with tetrabutylammonium cation as the phase-transfer catalyst and pentafluorobenzyl bromide as the alkylating agent, and employs a structural analog, d-3-hydroxy-N-ethylmorphinan, as the internal standard. The pentafluorobenzyl ethers formed are separated by capillary gas chromatography and detected by electron capture. The method has good precision and accuracy for concentrations ranging from 0.25 ng/ml to 100 ng/ml and has been used to measure plasma concentrations as part of a study to evaluate the management of chronic neuropathic pain with levorphanol.

A new human experimental pain model: the heat/capsaicin sensitization model.

The heat/capsaicin sensitization model is a new human experimental pain model that synergistically combines non-invasive physical and chemical methods of nociceptor stimulation to produce stable and long-lasting hyperalgesia with a low potential for skin injury. In 10 healthy volunteers the forearm was stimulated with a 45 degrees C thermode for 5 min to produce an area of secondary hyperalgesia. Applying capsaicin cream for 30 min further expanded the area of secondary hyperalgesia. Periodically heating the treated skin with a previously non-painful temperature of 40 degrees C re-kindled the sensitization enough to maintain stable areas of secondary hyperalgesia for 4h. The evoked pain was moderate and well tolerated. The heat/capsaicin sensitization model should be well suited for studying pain mechanisms and testing new analgesics.

Effect of EMLA pre-treatment on capsaicin-induced burning and hyperalgesia.

Capsaicin, which has been studied extensively as a treatment for itch and several chronic pain disorders, induces burning during the first week of therapy, causing a substantial percentage of patients to discontinue treatment prematurely. We examined whether pre-treatment with the topical anesthetic EMLA reduces the burning sensation induced by capsaicin and alters capsaicin effects on thermal sensation and pain thresholds. Healthy adult volunteers participated in the single-blind, 6-day study. After baseline measurement of warmth, cold pain and heat pain thresholds with a computerized thermal sensory analyzer, subjects applied EMLA thrice daily on one forearm and vehicle placebo on the other forearm, 60 min before applying capsaicin 0.075% on both forearms. Subjects rated burning sensations 3 times a day throughout the study. After 1 and 5 days of thrice daily application of EMLA or vehicle followed by capsaicin, thermal sensory testing was repeated. Subjects rated burning sensations to the significantly less on the EMLA pre-treated forearm compared with the placebo pre-treated forearm during all 5 days of treatment (p < 0.01). Capsaicin with and without EMLA produced significant heat pain hyperalgesia and cold pain hypoalgesia after 1 day of treatment. After 5 days of treatment, heat pain hyperalgesia persisted on both forearms; however, it was significantly less on the EMLA-treated forearm vs the vehicle-treated site (p < 0.03). Cold pain hypoalgesia persisted in both forearms. The warmth sensation threshold was significantly higher on the EMLA-pre-treated forearm after 1 and 5 days of treatment. In conclusion, pre-treatment with EMLA significantly reduced the burning sensation from capsaicin and attenuated heat hyperalgesia during treatment.

Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation.

BACKGROUND: Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear. OBJECTIVE: To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans. METHODS: In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger. RESULTS: The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited. CONCLUSIONS: Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin-induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present.

Cocaine metabolite kinetics in the newborn.

The study goal was to determine the half-life elimination of cocaine and benzoylecgonine (BZE) in the newborn. Three 0.3-mL blood samples were collected during the first day of life. Urine was collected once daily. Cocaine and BZE concentrations were determined by gas chromatography-mass spectrometry. An extraction method was developed for measuring low concentrations of cocaine and BZE in small (0.1 mL) blood samples. Cocaine had a half-life of 11.6 h in one subject. The half-life of BZE during the first day of life, based on blood data in 13 subjects, was 16 h (95% confidence interval [CI], 12.8 to 21.4 h). The half-life of BZE during the first week of life, based on urine data in 16 subjects, was 11.2 h (95% CI, 10.1 to 11.8 h). The novel extraction method for small blood sample volumes should be applicable to other basic drugs.

Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial.

CONTEXT: Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients. OBJECTIVE: To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997. SETTING: Sixteen US outpatient clinical centers. PARTICIPANTS: A total of 229 subjects were randomized. INTERVENTION: A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study. MAIN OUTCOME MEASURES: The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events. RESULTS: One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group). CONCLUSIONS: Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy.

Postherpetic neuralgia: irritable nociceptors and deafferentation.

Postherpetic neuralgia (PHN) is a common and often devastatingly painful condition. It is also one of the most extensively investigated of the neuropathic pains. Patients with PHN have been studied using quantitative testing of primary afferent function, skin biopsies, and controlled treatment trials. Together with insights drawn from an extensive and growing literature on experimental models of neuropathic pain these patient studies have provided a preliminary glimpse of the pain-generating mechanisms in PHN. It is clear that both peripheral and central pathophysiological mechanisms contribute to PHN pain. Some PHN patients have abnormal sensitization of unmyelinated cutaneous nociceptors (irritable nociceptors). Such patients characteristically have minimal sensory loss. Other patients have pain associated with small fiber deafferentation. In such patients pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (allodynia). In these patients, allodynia may be due to the formation of new connections between nonnociceptive large diameter primary afferents and central pain transmission neurons. Other deafferentation patients have severe spontaneous pain without hyperalgesia or allodynia and presumably have lost both large and small diameter fibers. In this group the pain is likely due to increased spontaneous activity in deafferented central neurons and/or reorganization of central connections. These three types of mechanism may coexist in individual patients and each offers the possibility for developing new therapeutic interventions.