The neuropathic component in persistent postsurgical pain: a systematic literature review.

Persistent postsurgical pain (PPSP) is a frequent and often disabling complication of many surgical procedures. Nerve injury-induced neuropathic pain (NeuP) has repeatedly been proposed as a major cause of PPSP. However, there is a lack of uniformity in NeuP assessment across studies, and the prevalence of NeuP may differ after various surgeries. We performed a systematic search of the PubMed, CENTRAL, and Embase databases and assessed 281 studies that investigated PPSP after 11 types of surgery. The prevalence of PPSP in each surgical group was examined. The prevalence of NeuP was determined by applying the recently published NeuP probability grading system. The prevalence of probable or definite NeuP was high in patients with persistent pain after thoracic and breast surgeries-66% and 68%, respectively. In patients with PPSP after groin hernia repair, the prevalence of NeuP was 31%, and after total hip or knee arthroplasty it was 6%. The results suggest that the prevalence of NeuP among PPSP cases differs in various types of surgery, probably depending on the likelihood of surgical iatrogenic nerve injury. Because of large methodological variability across studies, a more uniform approach is desirable in future studies for evaluating persistent postsurgical NeuP.

[Caffeine as adjuvant analgeticum for treating acute pain]. / Koffein som adjuverende analgetikum til behandling af akutte smerter ­ en gennemgang af et Cochranereview.

Based on 19 studies (7,238 participants) a Cochrane review concludes that the addition of caffeine to an analgesic drug provides superior analgesia compared with the analgesic drug alone. The benefit is small, with a number needed to treat of approx. 16. The use of analgesics containing caffeine is associated with an increased risk of the development of physical dependence, overuse headache, and withdrawal symptoms upon abrupt discontinuation. Combination analgesics with caffeine should only be used temporarily and exclusively for the treatment of acute pain conditions.

Methadone for chronic non-cancer pain in adults.

BACKGROUND: Methadone belongs to a class of analgesics known as opioids, that are considered the cornerstone of therapy for moderate-to-severe pain due to life-threatening illnesses; however, their use in chronic non-cancer pain (CNCP) is controversial. Methadone has many characteristics that differentiate it from other opioids, which suggests that it may have a different efficacy and safety profile. OBJECTIVES: To assess the analgesic effectiveness and safety of methadone in the treatment of CNCP. SEARCH METHODS: We identified both randomized controlled trials (RCTs) and non-randomized studies of methadone use in chronic pain by searching the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2011, issue 11, MEDLINE (1950 to November 2011), and EMBASE (1980 to November 2011), together with reference lists of retrieved papers and reviews. SELECTION CRITERIA: We included RCTs with pain assessment as either the primary or secondary outcome. Quasi-randomized studies, cohorts and case-control trials were also considered for inclusion because we suspected that the beneficial and harmful effects of methadone in CNCP may not be adequately addressed in RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted efficacy and adverse event data and assessed risk of bias. MAIN RESULTS: We included two RCTs and one non-randomized study, involving a total of 181 participants. Both RCTs were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes, the other involving 76 participants with postherpetic neuralgia. Study phases were 20 days and approximately eight weeks, respectively. The non-randomized study retrospectively evaluated 86 outpatients over an average of 8.8 ± 6.3 months.One RCT reported average pain intensity and pain relief, and found statistically significant improvements versus placebo for both outcomes, with 10 mg and 20 mg daily doses of methadone. The second RCT reported differences in pain reduction between methadone and morphine and found morphine to be statistically superior. The non-randomized study found that in patients initially prescribed methadone it was effective in fewer participants than in those initially prescribed other long-acting opioids (28% versus 42%, 33% and 50% for morphine, oxycodone and transdermal fentanyl, respectively).One RCT compared incidences for several individual adverse events, but found a difference between methadone and placebo for only one event, dizziness (P = 0.041). AUTHORS' CONCLUSIONS: The three studies provide very limited evidence of the efficacy of methadone for CNCP, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. No conclusions can be made regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.

Development and validation of shortened, restructured Treatment Outcomes in Pain Survey instrument (the S-TOPS) for assessment of individual pain patients' health-related quality of life.

Chronic pain produces major functional disability and quality-of-life impairment. Monitoring of health-related quality of life (HRQoL) outcomes in chronic pain patients during treatment is of great importance. Nevertheless, monitoring individual chronic pain patients remains a challenge due to the lack of a validated and efficient HRQoL assessment instrument. The Treatment Outcomes in Pain Survey (TOPS) is a validated HRQoL tool with sufficient accuracy and sensitivity to monitor the overall pain experience of individual patients while receiving multidisciplinary chronic pain management. However, the amount of time required to complete the TOPS questionnaire limits routine clinical utility and patient compliance. The full 14 TOPS scales are not needed to monitor routine clinical outcomes. Therefore, we developed and initially validated a shortened and restructured instrument, the S-TOPS, for individual patient monitoring in multidisciplinary chronic pain treatment. The reliability and validity of the S-TOPS were analyzed using data from 964 chronic pain patients who were treated in a single interdisciplinary pain clinic and completed >1 TOPS. The 7 scales of the S-TOPS have excellent construct validity, high reliabilities, and improved sensitivity to change for monitoring individual patient outcomes. Patients accepted the S-TOPS well, finding it brief enough for routine repeated administration.

Placental transfer of the insulin analog glargine in the ex vivo perfused placental cotyledon model.

OBJECTIVE: The aim was to characterize the transfer of the insulin analog glargine across the placenta using the placental perfusion model. METHODS: Placentas were obtained and selected cotyledons were cannulated and dually perfused. Glargine, 50 mU/L (n = 2) and 200 mU/L (n = 1), and a reference marker, antipyrine (50 µg/mL), were added to the maternal circulation. Samples were taken from the maternal and fetal compartments. RESULTS: Glargine was not detected in the fetal compartment. In the maternal compartment, the steady state concentration was 50% lower than the starting concentration. CONCLUSIONS: Glargine probably does not cross the human placenta. Reduced maternal steady state concentrations may suggest insulin uptake by the placenta.

Cost and comorbidities associated with opioid abuse in managed care and Medicaid patients in the United Stated: a comparison of two recently published studies.

Opioid abuse places a large burden on the U.S. society. Two similarly designed studies recently identified the economic and health impact of opioid abuse in patients with private or Medicaid insurance. The prevalence of opioid abuse was estimated to be over 10 times higher in Medicaid beneficiaries than private insurance populations, 87 versus 8 per 10,000, respectively. Opioid abusers incurred annual medical costs that were $14,054 to $6650 higher than nonabusers in patients with private insurance or Medicaid beneficiaries, respectively (P < .01 for both). Annual costs were similar for abusers with private insurance ($15,884) or Medicaid beneficiaries ($13,658). Costs for nonabuser Medicaid beneficiaries were $7008 versus $1830 for those with private insurance, which likely reflects the lower health status of the overall Medicaid population. In both studies, the prevalence of comorbidities associated with substance abuse or chronic pain were significantly higher in abusers than nonabusers. These studies confirm that opioid abuse is associated with comorbidities that increase direct medical costs for patients with private insurance and for Medicaid beneficiaries, increasing the societal burden of opioid abuse.

High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans.

BACKGROUND: Depot formulations prolong the analgesic effect of local anesthetics and reduce peak plasma drug concentration. This allows for safer administration of larger doses of local anesthetics, which further prolongs the duration of analgesic effect. We previously reported the development of large multivesicular vesicles (LMVVs) remotely loaded with bupivacaine (LMVV liposomal bupivacaine) and demonstrated a >5-fold prolongation of analgesic effect in animals and humans. In this study, we present pharmacokinetic data of LMVV liposomal bupivacaine in humans. METHODS: Healthy volunteers received subcutaneous injections of 20 mL plain 0.5% bupivacaine and, 1 week later, 20 mL of 2% LMVV liposomal bupivacaine in a prospective, open-label, crossover, controlled study. RESULTS: Eight subjects were studied. No subjective side effects of local anesthetics were observed. The maximal plasma concentration and the time to achieve maximal plasma concentration were assessed by modeling plasma concentration-time profiles. Maximal plasma concentration was not significantly different between groups (0.87 +/- 0.45 microg/mL and 0.83 +/- 0.34 microg/mL for plain and liposomal bupivacaine, respectively; P = not significant, 0.83). These values are well below the putative toxic plasma concentration of 2 to 4 microg/mL. Time to achieve maximal plasma concentration was 7-fold greater for the liposomal preparation (262 +/- 149 minutes vs 37.5 +/- 16 minutes, P < 0.01). CONCLUSIONS: Peak plasma bupivacaine concentrations were not different in the 2 groups, despite a 4-fold increase in total bupivacaine dose administered in the novel liposomal preparation. The delayed elimination and prolonged redistribution of liposomal bupivacaine to plasma is compatible with the depot-related slow-release effect leading to the prolonged pharmacodynamic effect previously reported.

Topical NSAID therapy for musculoskeletal pain.

OBJECTIVE: Systematic reviews previously reported in the literature document that topical nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in relieving pain in acute and chronic painful musculoskeletal disorders including osteoarthritis, tendonitis, and muscle strains. Because several topical NSAIDs are available, with important differences among the formulations, there is a need to address and summarize the evidence of their effectiveness and safety. DESIGN: We searched Medline and Cochrane CENTRAL databases for clinical trials and systematic reviews of topical NSAIDs in musculoskeletal pain, using the following keywords: "NSAID,""nonsteroidal,""antiinflammatory,""topical,""cream,""gel,""solution,""lotion,""patch,"plaster,""musculoskeletal,""tendonitis,""strain,""sprain,""trauma," and word roots "pain" and "arthritis." CONCLUSIONS: Topical NSAIDs may vary significantly in their absorption kinetics and pharmacodynamic effects, based on NSAID molecule and the formulation chosen. Some topical NSAID formulations have been shown to be more effective than placebo in multiple studies, or to have comparable efficacy and a better safety profile than oral NSAIDs for single joint osteoarthritis and acute muscle injuries. In acute and chronic low back pain, widespread musculoskeletal pain, and in peripheral neuropathic pain syndromes, the current evidence does not support the use of topical NSAIDs.

Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study.

Several case reports indicate that carbapenem antibiotics, especially meropenem, may decrease the plasma concentrations of valproic acid (VPA), thus decreasing its therapeutic activity. To investigate the onset, severity, and dose dependency of the interaction between meropenem and VPA, the authors carried out a retrospective evaluation of data collected during 24 months from patients hospitalized in a tertiary medical center. The analysis included 36 patients. VPA mean +/- SEM plasma concentration decreased from of 50.8 +/- 4.5 microg/mL to 9.9 +/- 2.1 microg/mL (P < .001) following meropenem administration. After discontinuation of meropenem, VPA plasma concentrations remained low for 7 days and then gradually increased after 8 to 14 days, reaching values comparable to those before meropenem initiation. Different daily VPA doses showed a similar pattern of decreased VPA concentrations. The mean decrease in individual plasma VPA concentration was 82.1% +/- 2.7%. The mean VPA plasma concentration of patients in whom samples were drawn within 24 hours of meropenem initiation was 9.9 +/- 3.2 microg/mL. In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly.

The challenge of pain management in patients with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. The complexity of the disease and its treatments make MG patients particularly susceptible to adverse effects of drugs. MG is not a painful condition; however, as pain management armamentarium includes drugs from diverse pharmacological groups and with potential for drug-drug interactions, managing pain in patients with MG can be challenging. The underlying disease and the concomitant medications of each patient must be considered and the analgesic treatment individualized. This review presents an update on the various aspects of pain pharmacotherapy in patients with MG, focusing primarily on medications used to treat chronic pain. Drugs discussed are opioids, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants, muscle relaxants, benzodiazepines, intravenous magnesium, and local anesthetics. Drug interactions with agents used for MG treatment (acethylcholinesterase inhibitors, corticosteroids, immunosuppressants) and plasmapheresis are discussed. The clinical usefulness and limitations of each of the drug classes and agents are described.

Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain.

Cannabinoids have been used for pain relief for centuries and recent studies have investigated their analgesic and anti-inflammatory mechanisms, as well as clinical efficacy, in treating chronic pain. We report an open-label study addressed to evaluate the effect and adverse events of orally administered Delta-9-tetrahydrocannabinol (Delta-9-THC) in 13 patients with chronic nonmalignant pain (CNMP) unresponsive to conventional pharmacotherapy. The effect of the treatment was assessed on an eight-item HRQoL questionnaire. Five out of 13 patients reported adequate response to the treatment while eight patients reported inadequate or no response. Seven patients did not experience any adverse events (AEs), six patients reported AEs, two of which discontinued the treatment. We conclude that oral THC may be a valuable therapeutic option for selected patients with CNMP that are unresponsive to previous treatments, though further research is warranted to characterize those patients.

Determination of metformin transfer across the human placenta using a dually perfused ex vivo placental cotyledon model.

OBJECTIVE: The aim of the study was to quantify and characterize metformin transfer across the human placenta using an ex vivo placental perfusion model. STUDY DESIGN: Placentas were obtained from vaginal deliveries or caesarean sections and selected cotyledons were cannulated and dually perfused. Metformin (1 microg/ml) and a permeability reference marker, antipyrine (50 microg/ml), were added to the maternal circulation. Each perfusion experiment was conducted for 180 min while samples were taken from the maternal and fetal compartments. The integrity and viability of the placenta were determined by measuring the flow rates, fetal artery inflow pressure, and hCG production during the experiments. RESULTS: Six complete experimental set-ups were completed. The maternal-fetal transport rates for metformin and antipyrine were 10.61+/-2.85% and 30.98+/-5.62%, respectively. The clearance index, calculated as the ratio between the permeabilities of metformin and antipyrine, was 0.34+/-0.05. CONCLUSION: The results indicate that metformin is able to cross the mature human placenta; thus, fetal exposure must be considered when treating pregnant women with metformin.

Rasagiline - a novel MAO B inhibitor in Parkinson's disease therapy.

Parkinson's disease (PD) is a progressive neurodegenerative, dopamine deficiency disorder. The main therapeutic strategies for PD treatment relies on dopamine precursors (levodopa), inhibition of dopamine metabolism (monoamine oxidase [MAO] B and catechol-O-methyl transferase inhibitors), and dopamine receptor agonists. Recently, a novel selective and irreversible MAO B propargylamine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect((R))) was approved for PD therapy. In contrast to selegiline, the prototype of MAO B inhibitors, rasagiline is not metabolized to potentially toxic amphetamine metabolites. The oral bioavailability of rasagiline is 35%, it reaches T(max) after 0.5-1 hours and its half-life is 1.5-3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5-1 mg once-daily as adjunctive to levodopa in advanced PD patients. Rasagiline treatment was not associated with "cheese effect" and up to 20 mg per day was well tolerated. In PD patients with hepatic impairment, rasagiline dosage should be carefully adjusted. Rasagiline should not be administered with other MAO inhibitors and co-administration with certain antidepressants and opioids should be avoided. Although further clinical evidence is needed on the neuroprotective effects of rasagiline in PD patients, this drug provides an additional tool for PD therapy.