Single-dose intravenous nefopam on postoperative catheter-related bladder discomfort in patients undergoing transurethral resection of prostate: a randomized, double-blind placebo-controlled trial.

PURPOSE: Transurethral resection of prostate (TURP) with postoperative catheter traction can lead to significant catheter-related bladder discomfort (CRBD). This condition causes many postoperative complications and low patient satisfaction. This study aimed to evaluate the effectiveness of preoperative single-dose intravenous nefopam on the incidence and severity of CRBD and its adverse effects. METHODS: This randomized, controlled, double-blind study included patients who underwent TURP under spinal anesthesia with postoperative urinary catheter traction. Patients were allocated into nefopam (NF) and normal saline (NS) groups. Twenty mg of nefopam in normal saline solution (NSS) 100 mL or NSS 100 mL were given intravenously before TURP. The primary outcome was the incidence of CRBD. RESULTS: Seventy-three patients were randomized into NF (n = 37) and NS (n = 36) groups. There were 35 and 33 patients in the NF and NS groups, respectively, in the final analysis. The incidences of CRBD were 45.71% and 84.85% in the NF and NS groups at 6 h after operation, respectively, OR 0.54 (95% CI 0.36, 0.73), while before the end of catheter traction, the corresponding incidences were 37.14% and 75.76%, respectively, OR 0.49 (95% CI 0.28, 0.84). The CRBD scores were statistically significantly lower in the NF group at both time points. Morphine consumptions and adverse effects were not different between groups. Patient satisfaction was higher in the NF group. CONCLUSIONS: Single-dose nefopam significantly reduced the incidence and severity of CRBD in patients undergoing TURP with urinary catheter traction at 6 h after the procedure and before the end of catheter traction without increasing the adverse effects.

A Comprehensive Review of the Diagnosis, Treatment, and Management of Postmastectomy Pain Syndrome.

PURPOSE OF REVIEW: Postmastectomy pain syndrome (PMPS) remains poorly defined, although it is applied to chronic neuropathic pain following surgical procedures of the breast, including mastectomy and lumpectomy in breast-conserving surgery. It is characterized by persistent pain affecting the anterior thorax, axilla, and/or medial upper arm following mastectomy or lumpectomy. Though the onset of pain is most likely to occur after surgery, there may also be a new onset of symptoms following adjuvant therapy, including chemotherapy or radiation therapy. RECENT FINDINGS: The underlying pathophysiology is likely multifactorial, although exact mechanisms have yet to be elucidated. In this regard, neuralgia of the intercostobrachial nerve is currently implicated as the most common cause of PMPS. Numerous pharmacological options are available in the treatment of PMPS, including gabapentinoids, tricyclic antidepressants, selective serotonin reuptake inhibitors, NMDA receptor antagonists, and nefopam (a non-opioid, non-steroidal benzoxazocine analgesic). Minimally invasive interventional treatment including injection therapy, regional anesthesia, botulinum toxin, and neuromodulation has been demonstrated to have some beneficial effect. A comprehensive update highlighting current perspectives on the treatment of postmastectomy pain syndrome is presented with emphasis on treatments currently available and newer therapeutics currently being evaluated to alleviate this complex and multifactorial condition.

Comparison of effect of electroacupuncture and nefopam for prevention of postanesthetic shivering in patients undergoing urologic operation under spinal anesthesia / 대한마취과학회지

BACKGROUND: Shivering during spinal anesthesia is a frequent complication and is induced by the core-to-peripheral redistribution of heat. Nefopam has minimal side effects and prevents shivering by reducing the shivering threshold. Electroacupuncture is known to prevent shivering by preserving the core body temperature. We compared the efficacies of electroacupuncture and nefopam for the prevention of shivering during spinal anesthesia. METHODS: Ninety patients scheduled for elective urological surgery under spinal anesthesia were enrolled in the study. Patients were randomly divided into the control group (Group C, n = 30), the electroacupuncture group (Group A, n = 30), and the nefopam group (Group N, n = 30). Groups C and A received 100 ml of isotonic saline intravenously for 30 minutes before spinal anesthesia, while Group N received nefopam (0.15 mg/kg) mixed in 100 ml of isotonic saline. Group A received 30 minutes of electroacupuncture before receiving anesthesia. Shivering scores, mean arterial pressure, heart rate, body temperature and side effects were recorded before, and at 5, 15, 30, and 60 minutes after spinal anesthesia. RESULTS: The incidence of postanesthetic shivering was significantly lower in Group N (10 of 30) and Group A (4 of 30) compared with that in Group C (18 of 30)(P < 0.017). Body temperature was higher in Group N and Group A than in Group C (P < 0.05). Hemodynamic parameters were not different among the groups. CONCLUSIONS: By maintaining body temperature during spinal anesthesia, electroacupuncture is as effective as nefopam in preventing postanesthetic shivering.

The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study.

PURPOSE: Nefopam is a widely available analgesic for the management of pain. The aim of this study was to reveal the effect of regional hyperthermia of the abdominal area on the pharmacokinetics of nefopam. MATERIALS AND METHODS: A randomised, single-dose, crossover, open-label study was conducted to reveal the effect of hyperthermia using modulated electro-hyperthermia on the pharmacokinetics of nefopam. The pharmacokinetics of orally administered nefopam without hyperthermia was studied in 12 healthy volunteers and then 7 days later they were treated with nefopam plus modulated electro-hyperthermia to the abdominal area for 1 h. Blood samples were collected up to 24 h after the drug administration. From the blood concentration-time curve, the maxinum plasma concentration (C(max)), time to C(max) (T(max)) and the area under the curve (AUC) were obtained. The safety and tolerability of these treatments were also assessed. RESULTS: The geometric mean ratios (GMRs) ((nefopam + modulated electro-hyperthermia)/nefopam) and the associated 90% confidence intervals (CIs) for C(max), AUC(last) and AUC(inf) were 1.2804 (1.1155∼1.4696), 1.0512 (0.9555∼1.1566) and 1.0612 (0.9528∼1.1819), respectively. The increase in C(max) was statistically significant, and T(max) was significantly shortened. CONCLUSIONS: The significant increase in C(max) and decrease in T(max) indicated that modulated electro-hyperthermia increased the absorption of the orally administered nefopam, thereby transitionally increasing the blood concentration of the drug. The AUC is an important parameter that contributes to the therapeutic effect of drugs. The lack of significant change in AUC suggests that modulated electro-hyperthermia may increases the absorption of orally administered drugs without increasing the systemic adverse effect of the drugs.

Efficacy and safety of neuromodulators in inflammatory arthritis: a Cochrane systematic review.

OBJECTIVE: To determine the efficacy and safety of neuromodulators for pain management in patients with inflammatory arthritis. METHODS: A Cochrane systematic review was performed as part of the 3e Initiative on pain management in inflammatory arthritis. We searched Medline, Embase, and Cochrane Central for studies to November 2010, and American College of Rheumatology/European League Against Rheumatism meeting abstracts published in 2008-2009. Studies were included if they were randomized or quasirandomized controlled trials that compared any neuromodulator (excluding cannabis) to another therapy (active or placebo, including nonpharmacological therapies) for pain in patients with RA, psoriatic arthritis, ankylosing spondylitis, or spondyloarthritis. Primary outcomes of interest were patient-reported pain relief of 30% or greater and withdrawals due to adverse events. Two authors independently extracted data and assessed methodological quality. A risk of bias assessment was performed using the methods recommended by the Cochrane Collaboration. RESULTS: Three trials, all in RA and all at high risk of bias, were included in this review. Two placebo-controlled trials evaluated nefopam (52 participants) and one placebo-controlled trial evaluated topical capsaicin 0.025% (31 participants). Pooled analysis showed a significant reduction in pain levels favoring nefopam over placebo after 2 weeks [weighted mean difference -21.2, 95% CI -35.6 to -6.7; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5]. However, nefopam was associated with significantly more adverse events (RR 4.1, 95% CI 1.6 to 10.7; number needed to harm 9, 95% CI 2 to 367), predominantly nausea and sweating. In one trial, capsaicin reduced pain more than placebo at 1 and 2 weeks (MD -23.8, 95% CI -44.8 to -2.8; NNT 3, 95% CI 2-47, and -34.4, 95% CI -54.7 to -14.14; NNT 2, 95% CI 1.4 to 6, respectively). Of those who received capsaicin, 44% developed burning at the site of application and 2% withdrew as a result. CONCLUSION: Based on 3 small trials, which were all at high risk of bias, there is weak evidence that nefopam and capsaicin are superior to placebo in reducing pain in patients with RA, but both are associated with a significant side effect profile. There are no available data for other types of IA or for newer agents such as gabapentin or pregabalin.

A high throughput screen identifies Nefopam as targeting cell proliferation in ß-catenin driven neoplastic and reactive fibroproliferative disorders.

Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of ß-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and ß-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42% of baseline in cell cultures from ß-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and ß-catenin protein level to 50% of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment. Nefopam caused a 45% decline in tumor number, 33% decline in tumor volume, and a 40% decline in scar size when tested in mice. There was also a 50% decline in ß-catenin level in-vivo. Nefopam targets ß-catenin protein level in mesenchymal cells in-vitro and in-vivo, and may be an effective therapy for neoplastic and reactive processes driven by ß-catenin mediated signaling.

Neuromodulators for pain management in rheumatoid arthritis.

BACKGROUND: Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. OBJECTIVES: The aim of this review was to determine the efficacy and safety of neuromodulators in pain management in patients with RA. Neuromodulators included in this review were anticonvulsants (gabapentin, pregabalin, phenytoin, sodium valproate, lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, tiagabine and topiramate), ketamine, bupropion, methylphenidate, nefopam, capsaicin and the cannabinoids. SEARCH METHODS: We performed a computer-assisted search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, 4th quarter), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44, 2010) and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 and 2009 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conference abstracts and performed a handsearch of reference lists of articles. SELECTION CRITERIA: We included randomised controlled trials which compared any neuromodulator to another therapy (active or placebo, including non-pharmacological therapies) in adult patients with RA that had at least one clinically relevant outcome measure. DATA COLLECTION AND ANALYSIS: Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of a neuromodulator on pain, depression and function as well as their safety. MAIN RESULTS: Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants).The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating.In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this.One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%). AUTHORS' CONCLUSIONS: There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.

Positive interference of the analgesic nefopam in the urine immunoassay for benzodiazepines in a secure setting.

An inpatient on a secure unit with a history of bipolar affective disorder and physical complaints including pain was prescribed carbamazepine, quetiapine, dihydrocodeine, nefopam, paracetamol and various aperients. A benzodiazepine urine test by immunoassay was positive. Initial literature searches did not suggest a candidate drug for positive interference. Other explanations were excluded. Positive results continued, despite room searches and other disruptive security measures. Further literature searches revealed one experimental series demonstrating positive interference of nefopam in the relevant assay. Benzodiazepine assays were negative after cessation of nefopam. This is the first such clinical case to our knowledge.

Postoperative nefopam and diclofenac. Evaluation of their morphine-sparing effect after upper abdominal surgery.

The aim of the study was to assess the relative morphine-sparing effects of nefopam and diclofenac when used singly or in combination after upper abdominal surgery. Eighty-four patients of ASA grade 1 or 2 were allocated randomly to one of three groups. Group A received nefopam 20 mg by intramuscular injection 6 hourly after surgery for the 24-hour study period. Group B received diclofenac 75 mg 12-hourly and placebo injections at 6 and 18 hours after surgery. Group C received both 6-hourly nefopam and 12-hourly diclofenac. Supplemental analgesia was given on demand via a patient-controlled analgesia system which delivered intravenous morphine. Morphine requirements in the diclofenac group were significantly lower than in either of the other groups (p less than 0.01). Patients who received the combination of nefopam and diclofenac required significantly less morphine than those who received nefopam alone (p less than 0.01). Pain scores assessed 6 hours after surgery were significantly lower in the diclofenac and combination groups compared with the nefopam group (p less than 0.01).

The need for analgesic cover after ENT surgery--comparison of nefopam and papaveretum.

Intra-operative intramuscular injections of either papaveretum 0.3 mg/kg or nefopam 0.4 mg/kg were given to alternate patients to promote smooth emergence from ENT anaesthesia in a consecutive series of 40 children. Observations over a period of 30 minutes following completion of surgery showed that emergence was satisfactory in 19 out of 20 children given papaveretum, and in 15 out of 20 children given nefopam. The study confirms that this indication for papaveretum is justifiably popular and that nefopam is a useful alternative mainly because it does not cause respiratory depression. There are no previous reports of the use of nefopam in children.

Electrophysiological investigations on the mode of action of nefopam, a novel analgesic agent.

The mode of action of nefopam, a novel analgesic, on the splanchnic afferent pathway was investigated using electrophysiological methods. Nefopam (2.5 and 5.0 mg/kg, i.v.) caused arousal patterns in spontaneous rabbit EEG. In intact cats, nefopam (1.0, 2.5 and 5.0 mg/kg, i.v.) suppressed the evoked potentials recorded from the posterior sigmoid gyrus of the cortex, N. ventralis posterolateralis and N. centralis medialis of the thalamus and the ventrolateral funiculus of the spinal cord following splanchnic nerve stimulation without inhibiting potentials in the thalamocortical pathways. These depressant effects were not antagonized by a narcotic antagonist, levallorphan (0.5 mg/kg, i.v.). The inhibitory effect of nefopam on the spinal potential evoked by splanchnic nerve stimulation was not observed in spinal cats (C1-C2 transection) and pentobarbital-anesthetized cats. These results suggest that nefopam may inhibit the splanchnic afferent pathways in the spinal cord by reinforcing descending inhibitory systems originating in the supra-spinal structure, in a manner which differs from that seen with morphine.

Analgesic studies with nefopam hydrochloride.

Nefopam hydrochloride[3] is a novel analgesic agent possessing an activity profile distinct from that of narcotic, narcotic agonist-antagonist and analgesic antiinflammatory agents. Analgesic activity is demonstrated in a variety of laboratory procedures with rodents, cats and monkeys. The analgesic potency of nefopam hydrochloride is generally similar to that of codeine phosphate. The compound lacks potential for tolerance development and does not exhibit cross-tolerance with morphine sulfate.