Injected morphine in postoperative pain: a quantitative systematic review

This systematic review of single-dose, placebo-controlled, randomized trials assessed pain relief from subcutaneous, intramuscular or intravenous morphine compared with placebo in postoperative pain. Pain relief or pain intensity difference over 4 to 6 hours was extracted and converted into the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. In 15 trials, comparing intramuscular morphine 10 mg (486 patients) with placebo (460 patients) morphine had an NNT of 2.9 (95% confidence interval 2.6-3.6). This meant that one of every three patients with moderate or severe postoperative pain treated with 10 mg intramuscular morphine had at least 50% pain relief, and would not have achieved this had they been given placebo. Minor adverse effects were more common with morphine (34%) than with placebo (23%) (relative risk 1.49 [1.09-2.04]), but drug related study withdrawal was rare (1.2% overall) and no different from placebo.     

Low-dose naloxone does not improve morphine-induced nausea, vomiting, or pruritus

OBJECTIVE: We tested the hypothesis that low-dose naloxone delivered with intravenous (IV) bolus morphine to emergency department patients in pain would reduce nausea. METHODS: Randomized, double-blind, placebo-controlled trial. Patients receiving 0.10 mg/kg morphine IV bolus rated pain, nausea, and pruritus on 100-mm visual analog scales at enrollment and 20 minutes. Patients were randomized to 0.25 microg/kg naloxone or equal volume placebo administered with IV morphine. RESULTS: One hundred thirty-one enrolled, 99 (76%) treated according to protocol with sufficient data for analysis. At 20 minutes the difference between groups (naloxone-placebo) was 1 mm (95% CI [confidence interval], -9 to 11) for nausea, 1 mm (95% CI, -3 to 3) for pruritus, 4% (95% CI, -1 to 9) for vomiting, and 0% (95% CI, -5 to 5) for rescue antiemetics. Pain was significantly reduced in both groups. CONCLUSION: Addition of 0.25 microg/kg naloxone to bolus morphine does not improve nausea, pruritus, vomiting, or reduce use of rescue antiemetics when administered to emergency department patients in pain.     

Effects of a single oral dose of desipramine on postoperative morphine analgesia

Drugs that block norepinephrine reuptake offer promise as opioid potentiators, because norepinephrine mediates opioid analgesia but not side effects such as sedation or nausea. In a two-by-two factorial design, we randomized 62 inpatients with pain following major surgery to receive either desipramine, 50 mg by mouth, or placebo at 6 a.m. on the first day after surgery. At their first request of pain medication after 8 a.m., they were given intravenous morphine, either 0.033 mg/kg or 0.10 mg/kg. Pain relief and side effects were assessed for 4 hr; peak relief on the visual analog scale (VAS) was the primary outcome variable. Pain relief, side effect scores, and time to remedication were significantly greater with the higher dose than with the lower dose of morphine, verifying assay sensitivity, but desipramine pretreatment did not significantly enhance morphine analgesia. The mean increase in peak VAS relief score after desipramine pretreatment, relative to placebo, was 6%; the 95% confidence interval for this estimate ranged from a 21% reduction to a 34% increase in pain relief. These results differ from a previous report that 1 week of pretreatment with desipramine, 75 mg per day, potentiated postoperative morphine analgesia. We conclude that if desipramine potentiation of opioid analgesia occurs in humans, its demonstration may require higher doses or chronic treatment.     

The effect of opioids on phantom limb pain and cortical reorganization

The efficacy of oral retarded morphine sulphate (MST) was tested against placebo in a double-blind crossover design in 12 patients with phantom limb pain after unilateral leg or arm amputation. Two counterbalanced treatment phases of 4 weeks each were initiated with an intravenous test infusion of MST or Placebo. The titration phase was 2 weeks. The dose of MST was titrated to at least 70 mg/day and at highest 300 mg/day. Pain intensity was assessed hourly on visual analog scales during a 4-week treatment-free phase, both treatment phases and at two follow-ups (6 and 12 months). Reorganization of somatosensory cortex, electric perception and pain thresholds as well as selective attention were measured pre- and post-treatment. A significant pain reduction was found during MST but not during placebo. A clinically relevant response to MST (pain reduction of more than 50%) was evident in 42%, a partial response (pain reduction of 25-50%) in 8% of the patients. Neuromagnetic source imaging of three patients showed initial evidence for reduced cortical reorganization under MST concurrent with the reduction in pain intensity. Perception and pain thresholds were not significantly altered whereas attention was significantly lower under MST. Thus, opioids show efficacy in the treatment of phantom limb pain and may potentially influence also cortical reorganization. These data need to be replicated in larger patient samples.     

Cannabinoid-opioid interaction in chronic pain

Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration-time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.     

Effectiveness of quinine in treating muscle cramps: a double-blind,placebo-controlled,parallel-group,multicentre trial

To determine the efficacy and safety of quinine in treating nocturnal muscle cramps we performed a double-blind, placebo-controlled, parallel-group, multicentre trial in 17 general practice centres in Germany. Ninety-eight patients aged 18-70 years with more than six muscle cramps in two weeks were enrolled. A two-week run-in period without treatment was followed by two weeks of treatment with 400 mg quinine or placebo per day and a wash-out period of two weeks without treatment. The primary outcome measure was the reduction in the number of muscle cramps between the run-in and treatment periods. The intensity of cramps, number of nights with cramps, sleep disturbance and intensity of pain were recorded as secondary outcome measures. At baseline the median number of cramps was 12 in two weeks in both groups. The median reduction between the run-in and therapy phases was eight (95% CI 7-10) versus six (95% CI 3-7) muscle cramps during quinine and placebo treatment; 36 (80%) participants in the quinine group and 26 (53%) in the placebo group had a reduction of at least 50% in the number of muscle cramps. Frequency, intensity and pain at night showed a statistically significant difference in favour of quinine. The improvement was more evident according to physician assessment than patient assessment; this is corroborated by the high placebo response rate. No significant differences were found between the two groups with respect to side-effects. Short term treatment with 400 mg quinine per day can effectively prevent nocturnal leg cramps in adults without relevant side-effects.     

High-dose tramadol in comparison to low-dose morphine for cancer pain relief.

Cancer pain treatment following the World Health Organization guidelines is effective and feasible. However, the evidence supporting the use of opioids for mild to moderate pain on the second step of the analgesic ladder is widely discussed. The present evaluation compares the efficacy and safety of high doses of oral tramadol (> or = 300 mg/d) with low doses of oral morphine (< or = 60 mg/d). Patients were included in this nonblinded and nonrandomized study if the combination of a nonopioid analgesic and up to 250 mg/d of oral tramadol was inadequate. 810 patients received oral tramadol for a total of 23,497 days, and 848 patients received oral morphine for a total of 24,695 days. The average dose of tramadol was 428 +/- 101 mg/d (range 300-600 mg/d); the average dose of morphine was 42 +/- 13 mg/d (range 10-60 mg/d). Additional nonopioid analgesics were given on more than 95% of days. Antiemetics, laxatives, neuroleptics, and steroids were prescribed significantly more frequently in the morphine group; the use of other adjuvants was similar in both groups. The mean pain intensity on a 0-100 numerical rating scale (NRS) was 27 +/- 21 (95% CI 26-29) in the tramadol and 26 +/- 20 (95% CI 24-27) in the morphine group (NS). The analgesic efficacy was good in 74% and 78%, satisfactory in 10% and 7%, and inadequate in 16% and 15% of patients receiving tramadol and morphine, respectively (NS). Constipation, neuropsychological symptoms, and pruritus were observed significantly more frequently with low-dose morphine; other symptoms had similar frequencies in both groups. These data suggest that tramadol can be used for the treatment of cancer pain, when nonopioids alone are not effective. High doses of tramadol are effective and safe.     

Chronic pain and sensory changes after augmentation mammoplasty: long term effects of preincisional administration of methylprednisolone

We studied the prevalence of chronic pain and long term sensory changes after cosmetic augmentation mammoplasty and the effects of a single i.v. preoperative dose of methylprednisolone 125 mg (n=74), parecoxib 40 mg (n=71), or placebo (n=74). A questionnaire was mailed 6 weeks and 1 year after surgery. Response rate after 1 year was 80%. At 1 year non-evoked pain was present in 13%, and evoked pain was present in 20% with no statistically significant differences between the groups. Methylprednisolone was associated with reduced odds for hyperesthesia at 1 year (OR 0.3, 95% CI 0.1-0.6), and significantly reduced the prevalence of hyperesthesia (30%) compared with placebo (56%, P<0.01) and parecoxib (51%, P<0.04). Factors associated with increased odds for pain at 1 year were intensity of pain during the first 6 days after surgery (OR 1.3, 95% CI 1.1-1.6), pain at 6 weeks (OR 18.4, 95% CI 6.9-49.3), hyperesthesia at 6 weeks (OR 2.3, 95% CI 1.1-5.1) and present hyperesthesia (OR 3.1, 95% CI 1.4-6.7). We conclude that persistent pain and sensory changes are common after augmentation mammoplasty, and that patients having pain at 6 weeks most likely will have pain also at 1 year. Acute postoperative pain, hyperesthesia at 6 weeks, and the presence of hyperesthesia increased the odds for pain at 1 year. Preoperative methylprednisolone resulted in significantly less hyperesthesia compared with both parecoxib and placebo, but did not significantly reduce the prevalence of persistent spontaneous or evoked pain.     

Efficacy and safety of lornoxicam compared with placebo and diclofenac in acute sciatica/lumbo‐sciatica: an analysis from a randomised,double‐blind,multicentre, parallel‐group study

Aim: The efficacy and safety of oral lornoxicam (LNX) as early treatment of acute sciatica/lumbo‐sciatica was compared with placebo and diclofenac in a 5‐day double‐blind, randomised study. Methods: Male or female patients (n = 171) aged 18–70 years with acute sciatica or lumbo‐sciatica [acute sciatica defined as typical radiation of pain along the sciatic nerve (including radiating pain below the knee) and worsening of pain as defined by Lasegue’s leg‐raising test (< 60°) within 72 h and previous attack ceased > 3 months previously; lumbo‐sciatica defined as symptoms of sciatica with concurrent lumbar pain and a predefined minimum pain score]. The dosage of study treatment was 8–24 mg/day LNX, 100–150 mg/day diclofenac or placebo. The primary end‐point was the difference in pain intensity difference from baseline to 6 h (PID_{0–6 h}) after the first dose of study treatment. Secondary end‐points were pain relief, the cumulative sums of pain intensity difference and total pain relief on day 1 and on days 2–4. Results: In total, 164 patients completed the study. Significant differences in PID between LNX and placebo were seen in the time interval 3–8 h after the first dose including PID_{0–6 h} (p = 0.015). Secondary end‐points favoured LNX vs. placebo, but in general were not significantly different. LNX and diclofenac had similar analgesic effect. Incidence and severity of adverse events were comparable for the three treatments; overall tolerability was rated as very good/good by 93% of the patients. Conclusion: These data indicate that the analgesic efficacy of LNX is superior to placebo and similar to diclofenac in acute sciatica/lumbo‐sciatica.     

Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects

Ultralow doses of naloxone (0.001-0.1 microg/kg) produce analgesia in animal models. However, no clinical study has evaluated the combination of ultralow dose naloxone and morphine using patient-controlled analgesia (PCA). This randomized, double blind controlled study sought to determine if the combination of ultralow dose naloxone and morphine in PCA solutions affects opioid requirements, analgesia, and side effects. Two-hundred and sixty-five patients (18-65 years old) undergoing operations were randomized to receive PCA morphine 1 mg/ml (n=129) or PCA morphine 1 mg/ml plus naloxone 0.6 microg/ml (n=136). We evaluated the numbers of supplemental rescue doses, the cumulative dose of each PCA solution, pain intensity, pain relief, and opioid side effects during the first 24 h after surgery. We found that opioid requirements did not differ significantly between groups. The morphine+naloxone group on average required 0.07 mg more morphine (95% CI -1.1 to 1.3) during the 24 h than the morphine group. Pain intensity levels were also similar in both groups. The morphine+naloxone group had 0.06 units lower (95% CI -0.5 to 0.4) pain intensity levels than the morphine group. The morphine+naloxone group had a lower incidence of nausea and pruritus than the morphine group (P=0.01 for both symptoms). However, the incidence of vomiting, time to tolerate fluids, sedation, and urinary retention were similar between groups (all P values >0.1). The combination of ultralow dose naloxone and morphine in PCA does not affect analgesia or opioid requirements, but it decreases the incidence of nausea and pruritus.     

Preoperative lumbar epidural morphine improves postoperative analgesia and ventilatory function after transsternal thymectomy in patients with myasthenia gravis

OBJECTIVE: To test the hypothesis that preoperative lumbar epidural morphine improves postoperative pain control and ventilatory function after transsternal thymectomy in patients with myasthenia gravis. DESIGN: The study design was randomized, placebo-controlled, and double-blind. SETTING: After surgery, all patients were admitted to the Neuroscience Critical Care Unit for evaluation and treatment. PATIENTS: All patients with myasthenia gravis who presented to the hospital for thymectomy were asked to participate in the study. Twenty patients were randomized to either the placebo or epidural morphine groups. INTERVENTIONS: Patients received either epidural morphine (7 mg in 14 mL of sterile saline) or saline (14 mL) before induction of anesthesia. Supplemental iv opioids were administered intraoperatively, with need determined by the anesthesiologist. MAIN OUTCOME MEASURES: The main outcome measures were indicators of postoperative pain (e.g., Visual Analog Pain Score, requirement for supplemental opioid administration, respiratory rate) and ventilatory function (e.g., forced vital capacity, negative inspiratory pressure). RESULTS: Immediately after surgery, the Visual Analog Pain Score in the placebo group was twice as high as the score in the epidural morphine group (placebo 7.0 +/- 1.3; epidural morphine 3.5 +/- 1.2, p less than or equal to .05). During the first eight postoperative hours, the placebo group required more opioids (0.22 +/- 0.03 vs. 0.12 +/- 0.04 mg/kg morphine equivalents, p less than or equal to .06) than the epidural morphine group. Later, both groups received similar amounts of opioids. Patients receiving epidural morphine had better initial recovery of forced vital capacity (at 8 hrs: 55 +/- 6% [epidural morphine] vs. 34 +/- 5% [placebo] of preoperative value, p less than or equal to .05). Respiratory rate was lower for the first 12 postoperative hours in the epidural morphine group, without a difference in PaCO2. There was no difference between groups for the duration of postoperative intubation or ventilation. CONCLUSIONS: Preoperative lumbar epidural morphine facilitates postoperative analgesia and improves initial postoperative ventilatory performance.     

Analgesic effects of dextromethorphan and morphine in patients with chronic pain

N-methyl-aspartate (NMDA) receptor antagonists have been shown to improve opioid analgesia in the animal model. The cough suppressant dextromethorphan is a clinically available NMDA-receptor antagonist. In this randomised, double-blind, placebo-controlled study 20 patients with chronic pain of several years duration were given 100 mg of oral dextromethorphan or matching placebo 4 h prior to an intravenous infusion of morphine 15 mg. Pain intensity and adverse effects were assessed at 0, 4, 5 and 7 h. Dextromethorphan had no effect on morphine analgesia: the mean (+/-SEM) visual analogue scores for pain relief (VAS, 0-100 mm) at the end of the morphine infusion were 38 (+/-6) for dextromethorphan+morphine and 38 (+/-7) for placebo+morphine. VAS scores for pain intensity were comparable both at rest and at movement at all time points. The most common adverse effects reported were dizziness, nausea and sedation. There were no significant differences in either the incidence or severity of adverse effects. In conclusion, oral dextromethorphan 100 mg had no effect on pain relief by intravenous morphine 15 mg in patients with chronic pain.     

Combination Drug Therapy for the Management of Low Back Pain and Sciatica: Systematic Review and Meta-Analysis

Combining medicines may give greater pain relief and/or improved tolerability. We conducted a systematic review to investigate the effects of combination drug therapy in patients with low back pain and/or sciatica on pain, disability, and adverse events. Databases and trial registers were searched from inception to July 27, 2017, for randomized trials of (sub)acute or chronic back pain or sciatica participants that were administered combination drug therapy compared with monotherapy or placebo. Of the 27 studies included, most combinations (21 of 23) consisted of single trials. Most combinations had no or small effect on pain and disability. A clinically important difference was found in one combination, buprenorphine plus pregabalin versus buprenorphine for chronic back pain at immediate (mean difference = –23.30; 95% confidence interval?=?–27.68 to –18.92) and short (mean difference?=?–27.60; 95% confidence interval?=?–31.70 to –23.50) terms; however, the quality of evidence was low. There was no statistically significant increased risk of serious adverse events. When the risk of adverse events was statistically significant, it favored monotherapy or placebo. There is no clear evidence to support any combination drug therapy for the management of low back pain and sciatica due to the limited number of studies and overall low quality of evidence.Perspective: Combining medicines may give greater pain relief and/or improved tolerability compared with single-ingredient medicines. However, the lack of studies and overall low quality of evidence limit the recommendation of combination drug therapy for the management of low back pain and sciatica.     

Cocaine and morphine interaction in acute and chronic cancer pain

An evaluation of the analgesic, mood and side effects of the combination of intramuscular morphine and oral cocaine was conducted in 17 patients with postoperative pain and 19 others with chronic malignant pain for the purpose of assessing the therapeutic merits of so-called 'euphoriant' elixirs in the management of pain in cancer patients. The study was designed as a randomized and double-blind single dose but complete cross-over comparison of the combination of 10 mg intramuscular morphine and 10 mg oral cocaine with morphine alone, cocaine alone, and placebo. While patients clearly discriminated between the analgesic effects of morphine and placebo, there were no differences in the analgesic responses to cocaine and placebo, or in responses to morphine and the combination of morphine and cocaine in either patient group. Side effects were predominantly morphine-like and occurred in 59% of patients after the combination, 43% after morphine, 34% after cocaine and 25% after placebo. Interaction effects between cocaine and morphine were observed in terms of positive changes toward selected aspects of mood (e.g., cheerful, friendly) in postoperative patients but toward negative aspects of mood (e.g., sad, serious) in patients with chronic pain.     

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans

OBJECTIVE: Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin-converting enzyme (ACE) inhibitor AVE7688. METHODS: We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo-controlled crossover study in sodium-depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin-angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium-replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. RESULTS: The 24-hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803-1052 nmol], P < .05) than after 5 mg AVE7688 (706 nmol [95% CI, 612-813 nmol]) or 10 mg ramipril (511 nmol [95% CI, 440-593 nmol]). The 25-mg dose of AVE7866 significantly and transiently (4 to 8 hours after drug intake) increased urinary ANP (2.02 +/- 1.05 ng/h, P < .05), whereas 5 mg AVE7688 (1.14 +/- 0.77 ng/h) and 10 mg ramipril (0.93 +/- 0.65 ng/h) had no effect compared with placebo (0.80 +/- 0.37 ng/h). In the low-salt panel the rise in plasma active renin concentration achieved 24 hours after dosing by 25 mg AVE7688 (247 pg/mL [95% CI, 157-389 pg/mL], P < .05) was significantly higher than that achieved by 5 mg AVE7688 (129 pg/mL [95% CI, 75-221 pg/mL]) or 10 mg ramipril (113 pg/mL [95% CI, 67-193 pg/mL]), which did not differ. In the high-salt panel group the effects of 25 mg AVE7688 on renin release did not significantly differ from those after administration of the combination of 150 mg irbesartan plus 10 mg ramipril or 300 mg irbesartan alone. All of these active drugs similarly decreased blood pressure compared with placebo. CONCLUSION: AVE7688 at a dose of 25 mg has a favorable pharmacodynamic profile compared with other RAS blockers. These results support further clinical studies of its long-term effects in essential or resistant hypertension, chronic proteinuric nephropathy, and chronic heart failure.     

Spinalanästhesie bei der Arthroskopie des Kniegelenks

BACKGROUND AND OBJECTIVE: Intrathecal morphine provides effective postoperative analgesia but is associated with the risk of respiratory depression. A dose of only 0.1 mg has been shown to be optimal for effective and safe pain relief after abdominal surgery. This study was designed to determine whether the addition of 0.1 mg of morphine to the local anesthetic for spinal anesthesia produces adequate analgesia following arthroscopic knee joint surgery. METHODS: A prospective, randomized, placebo-controlled, double-blind clinical trial was performed. Forty ASA I/II patients undergoing knee arthroscopy under spinal anesthesia were randomized to receive either mepivacaine 4% with 0.1 mg of morphine or mepivacaine 4% with saline (placebo) intrathecally. Postoperative analgesia consisted of intravenous morphine delivered by patient-controlled analgesia (bolus: 2 mg, lockout time: 5 min). During the study period of 24 h, pain intensity at rest and on movement (visual analogue scale, 0: no pain, 100: maximum pain), vigilance, and vital parameters were recorded every hour. RESULTS: There were no statistically significant differences between the two groups in postoperative pain scores, morphine requirements, vigilance, blood pressure, heart rate, and breathing frequency. The patients of the morphine group required 12.3+/-10.2 mg (mean+/-SD) and those of the placebo group 11.6+/-8.4 mg of intravenous morphine from patient-controlled analgesia. The pain scores at rest and on movement were 10.0+/-8.1 and 16.0+/-12.6 in the morphine group and 8.2+/-7.9 and 11.7+/-11.3 in the placebo group. We did not observe severe side effects in any of the patients. CONCLUSION: Intrathecal administration of 0.1 mg of morphine does not contribute to postoperative analgesia after arthroscopic knee joint surgery.     

Long-term intrathecal infusion of drug combinations for chronic back and leg pain

Continuous intrathecal infusion of analgesic drugs by implantable pumps is recognized as an established treatment option for patients with chronic pain resistant to oral or parenteral medication. Polyanalgesia, the simultaneous use of more than one intrathecal analgesic drug, is practiced relatively often, but there are only a few published clinical studies on intrathecal polyanalgesia for chronic nonmalignant pain. This pilot study represents a long-term evaluation of a treatment regimen consisting of intrathecal morphine admixed with bupivacaine, clonidine, or midazolam in patients with chronic nonmalignant back and leg pain due to degenerative lumbar spinal disease. Twenty-six adult patients have been treated by intrathecal programmable pump-controlled infusion of analgesic drugs and followed for up to 3.5 years (27 +/- 11 months). Combination of morphine with a second drug was used in 10 cases, morphine with 2 additional drugs in 12 cases, and morphine with 3 additional drugs in 4 cases. Mean daily doses at 24 months after pump implantation were 6.2 +/- 2.8 mg for morphine, 2.5 +/- 1.5 mg for bupivacaine, 0.06 +/- 0.03 mg for clonidine, and 0.8 +/- 0.4 mg for midazolam. Nineteen patients reported excellent or good long-term treatment results, 6 patients had sufficient results, and only 1 patient complained of poor therapeutic efficacy. No long-term clinical side effects of intrathecal polyanalgesia were noted. Mean morphine dose had to be increased from 1.2 mg at baseline to 5.1 mg at 24 months due to tolerance development and disease progression. This experience suggests that intrathecal polyanalgesia employing morphine combined with additional nonopioid drugs can have a favorable analgesic efficacy in patients with complex chronic pain of spinal origin, and lacks major drug-related complications.     

Retrospective consideration of the doses of morphine given intrathecally by chronic infusion in 163 patients by 19 physicians

A retrospective, multi-physician survey was carried out to examine the infusion concentrations of morphine delivered intrathecally by continuous infusion pumps placed to control pain. Replies from 19 physicians formed the basis for a population of 163 patients who received morphine by continuous infusion delivered by an Infusaid pump through a chronically implanted intrathecal catheter (N = 130 for pain of a metastatic origin; N = 3 for non-metastatic pain; N = 30 undefined). These patients received a total of 3443 patient weeks of infusion. The median infusion duration was 13 weeks (+/- 1 quartile: 5-24 weeks). Examination of the concentrations employed revealed that the maximally employed concentration was 1 mg/ml (885 patient weeks). Of the 163 patients, 151 patients received no concentration of morphine sulfate higher than 10 mg/ml. The highest reported concentrations used were around 35 mg/ml. No pathological sequelae related to the infusion of any dose of the opiates were reported. Cumulating the experience with morphine solutions of 8.9 and 10 mg/ml reveals a total of 472 patient weeks in 29 patients. Analysis of the change in infusion dose over time in cancer pain patients revealed a prominent time-dependent increase (N = 130) from 4.8 +/- 0.4 mg/day (N = 130) to 21 +/- 9 mg/day at 52 weeks (N = 10; mean +/- S.E.M.). Though the group morphine utilization rose, examination of the patient population which was infused for periods in excess of 3 months indicated that 48% showed less than a 2-fold increase in dose by 3 months.     

Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol

OBJECTIVE: Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. METHODS: With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double-blind, placebo-controlled, 4-way crossover study by use of experimental pain models. RESULTS: With paroxetine pretreatment, the area under the plasma concentration-time curve (AUC) of (+)- and (-)-tramadol was increased (37% [P = .001] and 32% [P = .002], respectively), and the corresponding AUCs of(+)- and (-)-M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)-M1 and (-)-M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus -84 kPa (95% CI, - 492 to -32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, -4.2 cm x s (95% CI, -6.8 to -1.9 cm x s) versus -0.4 cm x s (-1.4 to 1.4 cm x s) (P = .002); and discomfort, -4.7 cm (95% CI, -10.6 to -2.8 cm) versus 0.5 cm (-0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, -2.2 cm x s (95% CI, -3.7 to -0.4 cm x s) (P = .036, compared with placebo/tramadol); and discomfort, -2.0 cm (95% CI, -5.6 to -1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect. CONCLUSIONS: It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests.     

Clinical Outcomes in Neurogenic Claudication Using a Multimodal Program for Lumbar Spinal Stenosis: A Study of 49 Patients With Prospective Long-term Follow-up

ObjectiveThe purpose of this study was to assess long-term outcomes of a 6-week multimodal program (manual therapy, exercises, and self-management strategies) in patients with neurogenic claudication due to degenerative lumbar spinal stenosis.MethodsThis study evaluated 49 patients with neurogenic claudication who completed a 6-week multimodal program between 2010 and 2013. Outcomes included Oswestry Disability Index (ODI), Zurich Claudication Questionnaire (ZCQ), and Numeric Rating Scale. Mean differences, paired t tests, and the Wilcoxon rank-sum test were used to compare outcomes at baseline, 6 weeks, and long-term follow-up.ResultsTwenty-three patients completed the follow-up questionnaire (47% response rate). Median follow-up was 3.6 years (interquartile range: 3.3-4.6). The mean age was 73.5 years (standard deviation: 8.5). Between baseline and long-term follow-up, there were statistically significant and clinically important improvements in disability (ODI: -23.7 [95% confidence interval (CI): -15.7 to -31.6]; ODI walking item: -1.96 [95% CI: -1.34 to -2.57]; ZCQ function scale: -0.42 [95% CI: -0.10 to -0.70]) and pain (leg pain: -3.53 [95% CI: -1.80 to -5.20]; ZCQ symptom scale: -0.71 [95% CI: -0.30 to -1.10]), but not low back pain (Numeric Rating Scale: -1.03 [95% CI: -1.00 to 3.10]). There was no statistically significant change in any outcomes between 6 weeks and long-term follow-up.ConclusionIn a sample of patients with neurogenic claudication participating in a 6-week multimodal program, clinically important improvements in leg pain and disability, but not low back pain while walking, were maintained in the long term (median duration of 3.6 years) when compared to baseline.