Arthritis Rheum. 2005 Jan;52(1):312-21.

Opioid use by patients in an orthopedics spine clinic.

Mahowald ML, Singh JA, Majeski P.

Minneapolis VAMC, and the University of Minnesota, Minneapolis.

OBJECTIVE: Concerns regarding the efficacy, toxicity, tolerance, dependence, and abuse of opioids have limited their use for patients with chronic spine pain. In our previous study of rheumatology clinic patients, opioid analgesics were found to be highly effective, produced only mild side effects, and had few instances of opioid abuse. The purpose of this study was to replicate our previous study in another large cohort of patients with nonmalignant pain due to well-defined spinal diseases. METHODS: Opioid use was studied in 230 orthopedics spine clinic patients by retrospective analysis of prescriptions for 3 years and cross-sectional analysis of efficacy and toxicity by patient interviews. Opioid use and stability of the daily dose over 3 years were derived from computerized pharmacy records. Medical records, operative reports, and radiographic studies were reviewed to determine the reason for dosage escalations and to detect instances of abuse or addiction behaviors. Patients were interviewed to determine the efficacy, frequency, and types of side effects and instances of obtaining opioids from sources outside the Veterans Affairs system. RESULTS: Opioids were prescribed for 152 of the 230 patients, for <3 months (short-term [STO]) in 94, >/=3 months (long-term [LTO]) in 58, and none in 72 (no opioid [NTO]). Medications prescribed were codeine, oxycodone, propoxyphene, tramadol, morphine, meperidine, fentanyl, or hydroxycodone, either alone or in combination. Interviews were completed in 72 STO, 50 LTO, and 45 NTO patients. Pain severity (0-10 scale) was not different in patients with different spinal pathologies. Opioids significantly reduced the back pain severity score from 8.3 +/- 1.5 to 4.5 +/- 2.2 (mean +/- SD). Mild side effects (most commonly, constipation and sedation) were reported by 58% of the opioid-treated patients but rarely caused them to stop taking the medication. There was no significant increase from the mean +/- SD initial opioid dosage of 5.0 +/- 12.2 30-mg codeine equivalents per day (30 mg oral codeine = 5 mg oral morphine) to the mean peak dosage of 7.9 +/- 12.5 and the mean recent dosage of 4.3 +/- 6.3, suggesting that tolerance to opioid analgesia did not appear to occur in these patients. Dosage escalations of >2 30-mg codeine equivalents occurred 19 times in 17 LTO patients and was due to worsening of the underlying painful condition, complications of spine surgery, or unrelated surgical or medical problems in all but 3 of them (5%). These 3 patients also displayed other abuse behaviors. Abuse behaviors were not more frequent in those with or without a history of abuse/addiction. CONCLUSION: This study provides data on the efficacy, toxicity, tolerance, and abuse or addiction behaviors with opioid therapy in a large cohort of patients in an orthopedics spine clinic. The results provide objective data from patients with well-defined spine diagnoses to challenge the position that opioid treatment is inappropriate for chronic nonmalignant pain. This study provides clinical evidence to support and protect physicians treating patients with chronic musculoskeletal diseases, who may be reluctant to prescribe opioids because of possible sanctions from regulatory agencies. More important, it will benefit patients by permitting them to receive these effective, safe medications.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15641058




Clin Ther. 2004 Nov;26(11):1774-82.

Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study.

Malonne H, Coffiner M, Sonet B, Sereno A, Vanderbist F.

Laboratoire de Physiologie et de Phannacologie, CP206-3, Institut de Pharmacie, Universite Libre de Bruxelles,1050 Bruxelles, Belgium.

BACKGROUND: Opioid analgesics may be a useful alternative in patients with osteoarthritis who have not responded to first-line treatment with acetaminophen and in whom nonsteroidal anti-inflammatory drugs are contraindicated, ineffective, or poorly tolerated. OBJECTIVE: This study compared the efficacy and tolerability of tramadol LP 200 mg, a new once-daily,sustained-release formulation, with those of placebo in patients with osteoarthritis of the hip or knee. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group study, patients with osteoarthritis of the hip or knee (European League Against Rheumatism criteria) were randomized to receive either tramadol LP 200 mg once daily or placebo for 14 days. The primary efficacy end point was the change from baseline to the end of the study in scores on the Huskisson visual analog scale for pain. Secondary end points were change in the Lequesne functional discomfort index, global efficacy assessed by the patient and the investigator, time to improvement, and use of acetaminophen as rescue analgesic medication. Global tolerability was assessed by both patients and investigators at the end of the study The number and severity of adverse events occurring during the study and for 2 weeks thereafter were also recorded. RESULTS: Two hundred thirty patients (167 women, 63 men) were evaluable for efficacy and safety Demographic data for the tramadol and placebo groups were as follows: mean (SD) age, 67.1 (7.1) and 66.4 (92) years, respectively; female sex, 72.1% and 73.1%; and mean body weight, 74.7 (13.6) and 74.6 (14.8) kg. All patients were white. The completer analysis included 197 patients (85 tramadol, 112 placebo). Pain was significantly reduced in the tramadol LP group compared with the placebo group on day 7 (P = 0.002) and day 14 (P = 0.010). In the patient's assessment of global efficacy, 77.6% (66) of the tramadol LP group reported improvement by day 14, compared with 59.8% (67) of the placebo group; in the investigator's assessment, the efficacy of tramadol LP was rated very good or good for 612% (52) of patients, compared with 30.4% (34) for placebo. Improvement was reported before day 7 in 882% (75) of patients in the tramadol LP group, compared with 65.2% (73) in the placebo group (P = 0.021); the mean time from the initiation of treatment to reported improvement was 3 days for tramadol LP and 6 days for placebo (P < 0.001). Rates of response (defined as > or =30% pain reduction between days 0 and 14) were 64.7% (55) for tramadol LP and 50.0% (56) for placebo (P = 0.039); no rescue medication was used by 60.0% (51) of the tramadol LP group and 36.6% (41) of the placebo group (P - 0.001). One or more adverse event was reported by 45.0% (50) of the tramadol LP group, compared with 193% (23) of the placebo group (P < 0.001). As would be expected with an opiate agonist such as tramadol, the most common adverse events with this agent involved the gastrointestinal system (nausea, 22.5% [25] of patients; vomiting, 17.1% [19]) and the central nervous system (somnolence, 11.7% [13]). CONCLUSIONS: In this study, tramadol LP 200 mg was significantly more effective than placebo in alleviating pain in patients with osteoarthritis of the hip or knee. It appeared to be relatively well tolerated for an opioid compound.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15639689




Proc West Pharmacol Soc. 2004;47:117-9.

Evidence of self-synergism in the antinociceptive effect of tramadol in rats.

de Pozos-Guillen AJ, Aguirre-Banuelos P, Arellano-Guerrero A, Hoyo-Vadillo C, Perez-Urizar J.

Facultad de Estomatologia, Universidad Autonoma de San Luis Potosi, Zona Universitaria CP 78290 San Luis Potosi SLP.

Tramadol is an atypical opioid with a complex mechanism of action including the synergistic interaction between the parent drug and an active metabolite. However, the local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of locally (subcutaneous) and systemically (intraperitoneal) dosed tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In the second phase of the formalin test, tramadol was active not only by the systemic (ED50 7.15+/-0.46 mg/kg i.p.) but also by the local route (ED50 134.6+/-25.1 microg/paw). The isobolographic analysis evidenced a "self-synergism" in the antinociceptive effect between the two routes of administration since the experimental ED50 (30.8+/-0.1 "dose units") of the combination was significantly lower than the theoretical ED50 (70.9+/-12.6 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since naloxone reversed the potentiation. The observed site-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15633629




Proc West Pharmacol Soc. 2004;47:113-6.

Effect of acute exposure to arsenic on formalin-induced nociception and tramadol-mediated antinociception in mice.

Aguirre-Banuelos P, Escudero-Lourdes C, Carrizales L, Diaz-Barriga F, Perez-Urizar J.

Facultad de Ciencias Quimicas, UASLP, San Luis Potosi, Mexico.

In vitro studies have suggested that arsenic can modify the activity of macrophages in the mouse producing an over-regulation of the COX-2 and increased concentrations of PGE2 in endothelial cells. These effects may lead in vivo to enhancement of inflammatory and painful responses. In this study we studied the effect of an acute intoxication with sodium arsenite (1, 5, 10, 36 and 100 nmol/kg s.c.) on the nociceptive response of mice in the formalin test. On the other hand, the effect of arsenic on the antinociceptive response mediated by tramadol was evaluated in mice administered with a single dose of the analgesic agent (10 mg/kg s.c.). Arsenic levels in the liver were measured as a marker of the intoxication degree. Our results indicated that the arsenic acute exposure increases the nociceptive behavior in mice in a dose-dependent manner. Accordingly, the exposure to arsenic partially blocked the analgesic effect of tramadol although no statistical differences were reached. These results support the previous in vitro evidences regarding the alterations in the inflammatory-painful processes produced by the acute exposure to arsenic. Moreover, our results suggest that the intoxication with arsenic might exacerbate the pathological state in inflammatory diseases.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15633628




Br J Anaesth. 2004 Dec 17

Tramadol as adjunct to psoas compartment block with levobupivacaine 0.5%: a randomized double-blinded study{dagger}

Mannion S, O'callaghan S, Murphy DB, Shorten GD.

Department of Anaesthesia and Intensive Care, Cork University Hospital, St Mary's Orthopaedic Hospital and University College Cork, Cork, Ireland.

BACKGROUND: Tramadol has been administered peripherally to prolong analgesia after brachial plexus and neuraxial blocks. Our aim was to evaluate the systemic and perineural effects of tramadol as an analgesic adjunct to psoas compartment block (PCB) with levobupivacaine. METHODS: In a randomized, prospective, double-blinded trial, 60 patients (ASA I-III), aged 49-88 yr, undergoing primary total hip or knee arthroplasty underwent PCB and subsequent bupivacaine spinal anaesthesia. Patients were randomized into three groups. Each patient received PCB with levobupivacaine 0.5%, 0.4 ml kg(-1). The control group (group L, n=21) received i.v. saline, the systemic tramadol group (group IT, n=19) received i.v. tramadol 1.5 mg kg(-1) and the perineural tramadol group (group T, n=20) received i.v. saline and PCB with tramadol 1.5 mg kg(-1). Postoperatively patients received regular paracetamol 6-hourly and diclofenac sodium 12-hourly. Time to first morphine analgesia, 24-hour morphine consumption, sensory block, pain and sedation scores and haemodynamic parameters were recorded. RESULTS: Time (h) to first morphine analgesia was similar in the three groups [mean (SD)]: group L, 11.2 (6.6); group T, 14.5 (8.0); group IT, 14.6 (6.8); P=0.35. Twenty-four-hour cumulative morphine (mg) consumption was also similar in the three groups [group L, 21.9 (10.1); group T, 19.8 (6.7), group IT, 16.5 (9.5)], as were durations of sensory and motor block. There were no differences in the incidence of adverse effects except that patients in group IT were more sedated at 14 h than group L (P=0.02). CONCLUSION: We conclude that our data do not support a clinically important local anaesthetic or peripheral analgesic effect of tramadol as adjunct to PCB with levobupivacaine 0.5%.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15608044