David A. Cherry

Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial

&NA; This study was designed to assess the efficacy and safety of pregabalin—a novel &agr;2‐&dgr; ligand with analgesic, anxiolytic, and anticonvulsant activity—for treating neuropathic pain in patients with post‐herpetic neuralgia (PHN). Two hundred and thirty‐eight patients were randomised into this multicentre, doubleblind, placebo‐controlled trial to receive 150 (n=81), 300 mg/day (n=76) pregabalin, or placebo (n=81) for 8 weeks. Among the exclusion criteria was failure to respond to previous treatment for PHN with gabapentin at doses ≥1200 mg/day. Endpoint mean pain scores were significantly reduced in patients receiving 150 or 300 mg/day pregabalin compared with placebo. Efficacy was observed as early as week 1 and was maintained throughout the study. Significantly more patients in both pregabalin groups (150 mg, 26%; 300 mg, 28%) were responders (≥50% decrease in mean pain score from baseline to endpoint) than in the placebo group (10%). Additionally, by week 1 and for the studys duration, 150 and 300 mg/day pregabalin significantly reduced weekly mean sleep interference scores. More pregabalin‐treated patients than placebo‐treated patients reported that they were ‘much improved’ or ‘very much improved’. Health‐related quality‐of‐life (HRQoL) measurements using the SF‐36 Health Survey demonstrated improvement in the mental health domain for both pregabalin dosages, and bodily pain and vitality domains were improved in the 300 mg/day group. The most frequent adverse events were dizziness, somnolence, peripheral oedema, headache, and dry mouth. Pregabalin efficaciously treated the neuropathic pain of PHN. Additionally, pregabalin was associated with decreased sleep interference and significant improvements in HRQoL measures.

A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer.

Eighteen patients suffering from cancer were entered into a study of the pharmacokinetics and efficacy of methadone and morphine in pain control. All patients had both clinical and radiological evidence of metastatic spread of their cancer and there were no significant differences in age, weight and sites of the primary cancer between the methadone (n = 9) and morphine (n = 9) groups. Blood opioid concentration, visual analogue pain scores (VAPS) and end-tidal percent carbon dioxide were measured before and after both an intravenous and oral dose of either methadone or morphine. Terminal half-lives (mean +/- S.D.) were 30.4 +/- 16.3 h and 2.7 +/- 1.2 h respectively for methadone and morphine while the clearance values (mean +/- S.D.) were 0.19 +/- 0.13 l/min and 1.16 +/- 0.47 l/min. The long half-life of methadone was associated with prolonged pain relief. However, the large variation in the half-life of methadone necessitated careful adjustment of the dosing interval in individual patients. There were pronounced differences in oral bioavailability between the two opioids: methadone, 79 +/- 11.7%, compared to morphine, 26 +/- 13% (mean +/- S.D.). Of greater clinical significance was the variability in these bioavailability estimates with a coefficient of variation of 15% for methadone compared to 50% for morphine. The combined effects of low and variable oral bioavailability for morphine may result in sub-therapeutic doses being administered as practitioners may be inhibited by the size of the effective oral morphine dose and may be confused by the variability in this dose compared to intramuscular doses. The initial oral dose of morphine varied from 15 mg 4 hourly to 150 mg 3 hourly, while the initial dose for methadone varied from 15 mg on alternate nights to 20 mg twice daily. There was no rapid escalation of daily opioid dose for either methadone or morphine when adequate pain control was provided rapidly at the start of treatment by the technique described in this study.

Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration

&NA; Fentanyl (1 &mgr;g/kg body weight) was administered intravenously and via a lumbar epidural catheter (in random order) on 2 separate occasions to 6 patients with chronic pain associated with non‐terminal disease states. Frequent blood samples were collected from an indwelling intravenous catheter and CSF samples were collected via spinal needles inserted in the cervical (C7‐T1 interspace) and lumbar (L3,4 interspace) regions at 0, 5, 10, 20, 30 and 45 min after fentanyl administration. The concentration of fentanyl in blood and CSF samples were quantified by a sensitive and selective gas‐liquid chromatography assay. Visual analogue pain scores (VAPS) were recorded every 5 min for the first hour. Coded syringes (one containing the appropriate fentanyl dose while the other contained an equivalent volume of saline) allowed the investigator administering the fentanyl and assessing VAPS to remain blinded as to which route of administration actually contained the fentanyl. There was minimal vascular uptake of fentanyl following epidural administration. Similarly, the permeation of fentanyl into cervical and lumbar CSF following intravenous administration was minimal and erratic such that only 4 of the 60 CSF samples had detectable fentanyl concentrations. In contrast, there was a rapid penetration of fentanyl across the dura mater following lumbar epidural administration. There was significantly fentanyl in lumbar CSF samples by 10 min in 5 patients, and by 20 min in all 6 patients. The mean maximum lumbar CSF concentration was 19.1 ng/ml, while the time associated with these maximum concentrations was 22.5 min. The mean maximum cervical CSF fentanyl concentrations were 10% of the lumbar CSF concentrations. Cervical CSF fentanyl concentrations exceeded 0.5 ng/ml in only 2 of the 6 patients. There was no consistent similarity between the VAPS and time with the two routes of fentanyl administration. However, VAPS always decreased following epidural administration. It is concluded that fentanyl is rapidly absorbed across the dura mater following epidural administration providing significant lumbar CSF concentrations. The fentanyl in lumbar CSF undergoes cephalad migration, albeit to a small extent, as a result of passive CSF flow. The high lumbar CSF fentanyl concentrations interact with the opioid receptors in the dorsal horn region of the spinal cord to provide pain relief. However, the role of cervical fentanyl concentrations to any pharmacological effects remains unresolved.

The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects

&NA; A transdermal formulation of fentanyl (TTS‐fentanyl, Alza Corp., Palo Alto, CA) was evaluated in 13 surgical patients after an abdominal operation. An intraoperative dose of fentanyl (100–200 &mgr;g i.v.) was administered at the same time as the TTS‐fentanyl systems (50–125 &mgr;g/h) were applied to the antero‐lateral chest wall. The TTS‐fentanyl systems remained in situ for 24 h and were then removed and a second lot of systems were applied to the contra‐lateral chest wall. There was a mean (S.D.) delay time of 12.7 (9.6) h before minimum effective blood fentanyl concentrations (MEC) were obtained from the systems and pseudo‐steady state was reached between 36 and 48 h. There was a decay time of 16.1 (7.1) h after the systems were removed for the blood fentanyl concentration to decrease to less than the mean MEC for the control of postoperative pain. There was marked variability between patients in the actual hourly fentanyl dose rate determined from the residual amount of fentanyl remaining in the system and the duration of application. Significantly more supplementary pethidine was administered for inadequate postoperative analgesia between 0 and 12 h compared to the 12–24, 24–36 and 36–48 h periods; this was consistent with the observed delay time. Three patients required a reduction in the hourly fentanyl dose rate because of bradypnoea while 1 patient required an increase in dose because of inadequate pain relief. Nausea was the most frequently reported side effect (85% of patients) while bradypnoea, drowsiness, unpleasant dreams and headache were also reported. These effects were due to the combined effects of a sustained blood fentanyl concentration and the intermittent supplementary pethidine doses. Side effects due to the topical formulation were transient and included erythema (8 patients) and a minor rash (2 patients) in the area occluded by the systems. The TTS‐fentanyl systems provided a significant contribution to postoperative pain control but, at the TTS dose rates used, supplementary doses of pethidine were required by all patients probably to control ‘incident’ pain.

Long-term spinal administration of morphine in cancer and non-cancer pain: a retrospective study

&NA; Records of 313 patients who had been treated with spinal morphine via an implanted Port‐A‐Cath were reviewed. In 284 cases the Port‐A‐Cath was implanted for epidural delivery of morphine in patients with cancer‐related pain. These patients were treated for a mean of 96 (range 1–1215) days. There was a wide variation in dose requirements, minimum daily dose ranging from 0.5 to 200 mg and maximum daily dose from 1 to 3072 mg. However, there was no clear trend to increasing dose as period of epidural morphine administration increased. The most frequent complications were pain on injection (12.0% incidence), occlusion of the portal system (10.9%), infection (8.1%) and leakage of administered morphine such that it did not all reach the epidural space (2.1%). In all but 1 case infections were limited to the area around the portal or along the catheter track. All infections resolved without sequelae following removal of the portal and/or administration of antibiotics. In 17 patients Port‐A‐Caths were implanted for the intrathecal delivery of morphine to control cancer‐related pain. These patients also exhibited wide variations in morphine dose requirements. Port‐A‐Caths were also implanted for delivery of spinal morphine in 12 patients with chronic pain which was not related to cancer and which failed to respond to other therapies. These patients were treated for a mean of 155 (range 2–575) days. Port‐A‐Caths were removed from 7 of these patients, primarily due to infection (2 cases) and inadequate pain relief and pain on injection (2 cases).

Estimation of methadone clearance: application in the management of cancer pain

&NA; The long half‐life and wide inter‐patient variability in clearance of methadone make this drug difficult to use optimally. If a patients methadone clearance is known, however, dose regimens can be devised to maintain any desired blood concentration and hence, since the effect of methadone is related to its concentration in the blood, pain relief. We investigated methods for determining methadone clearance. In 25 patients, clearance was estimated by monitoring blood methadone concentrations following an intravenous infusion. Estimates of clearance adequate for clinical purposes could be obtained by assaying only 10–12 blood samples collected over 30 h following the infusion. The blood sampling schedules were such that it was not necessary to collect samples during the night, so the procedure could be done on an outpatient basis. An advantage of this procedure is that it also allows estimation of the blood methadone concentration required to relieve pain. We also conducted a retrospective study of data from 185 patients whose methadone clearance we had determined, to identify factors which may give rise to the large inter‐patient variation in clearance. Clearance tended to be high in patients taking phenytoin, spironolactone, verapamil or oestrogens, and low in patients taking amitriptyline. Patients with malignant disease as opposed to chronic benign pain, and patients 65 years of age or older, tended to have low clearance. Clearance was positively associated with haematocrit. An equation was constructed allowing methadone clearance to be predicted from knowledge of these factors. The predicted clearance, however, showed only a moderately strong correlation with measured clearance (r = 0.75), indicating that factors not investigated also had a major influence on methadone clearance.

Cephalad migration of morphine in CSF following lumbar epidural administration in patients with cancer pain

&NA; This study examines the cephalad migration of morphine in CSF following lumbar epidural administration in cancer patients with pain. Fourteen cancer patients were administered 10 mg of morphine in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2,3) and attached to a subcutaneously implanted portal for drug administration. There was a rapid vascular uptake of morphine from the epidural space with a mean (± S.D.) peak blood concentration of 110 ± 32 ng/ml (range 76–182 ng/ml and the mean time associated with this peak blood concentration was 5.1 ± 2.3 min (range 2–10 min). A cervical CSF sample was obtained from the C7−T1 interspace in each patient at one of the following times from the completion of the epidural morphine dose: 10, 30, 60, 120, 180, 240 or 360 min. There was a delay of at least 60 min before morphine was detected in significant concentrations (approximately 300 ng/ml) in the cervical CSF samples and peak CSF concentrations occurred after approximately 3 h. The results of this study are compatable with the hypothesis that the delayed onset of respiratory depression sometimes observed following epidural morphine in opioid naive patients results from significant amounts of morphine reaching the respiratory centre in the brain‐stem as a consequence of passive CSF flow in a rostral direction from the lumbar region.

The influence of drug polarity on the absorption of opioid drugs into CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine

&NA; This study examines the influence of drug polarity on the rate and extent of drug absorption into cerebrospinal fluid (CSF) following lumbar epidural administration. Twelve patients with pain secondary to cancer were simultaneously administered both morphine (10 mg) and pethidine (50 mg) in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L23) and attached to a subcutaneously implanted portal reservoir. Frequent blood samples were collected to characterise the vascular uptake of both opioids. In addition, a single CSF sample was collected in each patient from the C7–T1 interspace at one of the following times: 10, 30, 60, 120, 180 and 240 min. There was a rapid vascular uptake of morphine from the epidural space with a mean (± S.D.) peak concentration of 173 ± 80 ng/ml (range 52–345 ng/ml) and a time‐to‐peak concentration of 8 ± 6min (range 2–17 min). In contrast, the vascular uptake of pethidine was more variable with a mean ( ± S.D.) concentration of 274 ± 294 ng/ml (range 80–1113 ng/ml) and the time‐to‐peak concentration was 21 ± 26 min (range 2–75 min). There was a rapid absorption of pethidine across the dura mater into the CSF with peak CSF concentrations between 1400 and 1650 ng/ml occurring between 10 and 60 min in samples collected cephalad (C7–T1 interspace) from the administration point in the lumbar region. However, the peak morphine concentration in CSF was delayed relative to the pethidine peak and occurred at 120 min. The ratio of pethidine relative to morphine in the CSF samples progressively decreased from 76.5:1 in the 10 min sample to approximately 0.6–0.8:1 in the CSF samples obtained between 120 and 240 min. A ratio of approximately 5 (ratio of the two opioids in the injection solution) would be expected if both pethidine and morphine were absorbed from the epidural space and underwent cephalad migration at the same rate. This study suggests that drug polarity is an important variable in controlling absorption from the epidural space into CSF.

The efficacy of transdermal fentanyl in the treatment of postoperative pain : a double-blind comparison of fentanyl and placebo systems

&NA; Forty consenting patients scheduled for abdominal surgery were entered into a double‐blind comparison of the efficacy of transdermal fentanyl (TTS‐fentanyl) and placebo (TTS‐placebo) in the treatment of postoperative pain. All patients were allowed supplementary pethidine (25–50 mg) if pain relief was inadequate provided that their respiratory rate was > 10 breaths/min and there was no pronounced CNS depression. Visual analogue pain scores (VAPS), sedation rating scores (SRS), blood samples for the determination of fentanyl concentration, blood pressure, pulse and respiratory rate were determined hourly for 48 h from the time of TTS system application. The first lot of TTS systems were removed after 24 h and a second lot were applied which remained in situ for a further 24 h. There was no significant difference between the patients in the TTS‐fentanyl and TTS‐placebo groups in the VAPS throughout the 0–12, 12–24, 24–36 and 36–48 h periods suggesting that the quality of pain relief was similar between the 2 groups. However, significantly less supplementary pethidine was administered to the TTS‐fentanyl group in the 12–24, 24–36 and 36–48 h periods. In contrast, the amount of supplementary pethidine administered in the 0–12 h period was similar in both groups which was consistent with the long delay time (mean ± S.D. value of 16.6 ± 10 h) before clinically effective concentrations of fentanyl were obtained from the systems. The profile of side effects was similar in the 2 groups. There were only minor dermatological side effects (erythema and rash) which could be attributed to the formulation and these were not reported as troublesome by any of the patients. The mean measured release rate was similar to the nominal rate although there was considerable variability in the measured release rate at each dose level.

Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain.

Abstract Twenty‐four patients with severe pain related to cancer completed a randomised, double‐blind, double‐dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24‐h morphine dose was administered using two modified release oral morphine formulations; either one dose of KapanolTM (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin® (Purdue Frederick Company, Connecticut, USA) administered at 12‐h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead‐in period to provide the most favourable balance between pain relief and side‐effects. Patients were then randomly allocated to receive their 24‐h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side‐effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (±1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was ≥75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side‐effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side‐effects as 12‐h MS Contin.