Few medical practitioners or even those charged with over-seeing the medical profession, would argue the need for the appropriate use of opioid drugs in the management of acute pain associated with surgery or pain associated with cancer. However the use of opioids for non-cancer pain is controversial in many countries and is discouraged, even banned, in some countries where opiophobia thrives. The differentiation between the medical use of opioids to provide pain relief and the use of opioids to prevent withdrawal symptoms in those patients with either iatrogenic or self induced opioid abuse, is difficult for some legislators to follow - the easiest "solution" in these cases is to ban all opioids.In many western countries, most doctors, especially Pain Physicians, can see a role for the appropriate use of opioid drugs in the management of chronic non cancer pain. However there need to be strict guidelines agreed to by both doctors and legislators and protocols drawn up for the ongoing supervision of prescribing doctors and prescribed patients.The experience of opioid prescribing in Australia will be outlined. Even within Australia, with a relatively small population, there are significant differences between states in the manner in which opioids are prescribed. With the ready availability of computers and centralised databanks, the management of both prescribers and opioid users should be a relatively simple task.

Post herpetic neuralgia (PHN) is defined as pain present in the region of the body affected by herpes zoster (HZ) virus 3 months after the disappearance of the crusting lesions. PHN occurs in varying frequencies of those affected by HZ but the overall incidence is about 15%. The incidence increases with age and in immune compromised patients.Evidence is accumulating that suggests an immune type response where axons are further damaged by the release of cytokines in response to the initial HZ infection resulting in a further loss of neuronal integrity and a lowered firing threshold. This evidence in animals tends to support the clinical impression that patients with a decreased immune response are more likely to develop PHN.There may also be a genetic predisposition to the incidence of PHN following HZ as rats can be genetically modified such that either all or none of the rats develop a peripheral neuropathy following axotomy.The fact that there are so many therapies for PHN is testament to the fact that none of them are efficacious in more than a small percentage of cases. The various treatment regimens for PHN will be outlined but the advent of membrane stabilising drugs such as gabapentin and it's successor pregabalin, with a lower incidence of significant side effects does offer some hope.

This study was designed to assess the efficacy and safety of pregabalin—a novel α2-δ 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 study's 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.

With the advent of blood morphine assay techniques, it is possible to be more objective about the status of a patient with respect to morphine tolerance. It is not the total/24 hours oral morphine dose that is important but the resultant blood morphine level that determines whether the patient's pain behaviour is morphine sensitive or morphine resistant.Our Pain Unit has built up a database of patients receiving either morphine or methadone [1] and has, based on the responses of chronic non cancer pain sufferers, somewhat empirically used a blood morphine level between 50 and 150 ng/ml as being the therapeutic level. The therapeutic blood level for methadone is the same as for morphine as, molecule for molecule, they have the same analgesic effect.The term dependence is loosely used by both medical and non medical people but strictly refers to the onset of opioid withdrawal symptoms on the sudden cessation of the opioid drug. This has no relationship to addiction (the use of an opioid drug for non pain relieving reasons).Physical dependence refers to the need of chronic opioid users (whether it is by medical or recreational users) to have opioid substances occupying the opioid receptors - otherwise abstinence will occur.Psychological dependence refers to those recreational users of opioid drugs who use the opioids sporadically.

Collagen is the main component of connective tissue surrounding adipocytes. Collagen cross-linking affects adipose remodeling, which is crucial for maintaining function and metabolic homeostasis of adipose tissue. However, the effects of obesity on collagen cross-linking and adipose fibrosis remain to be examined. Therefore, the objective of this study was to investigate obesity-induced collagen cross-linking in adipose tissue and explore the underlying mechanisms. We found that obesity increased mature nonreducible collagen cross-linking in white adipose tissue (WAT) of mice, which was associated with inhibition of AMPK, up-regulation of transforming growth factor-β (TGF-β) signaling and the expression of lysyl oxidase (LOX), a key enzyme catalyzing the synthesis of mature cross-linking products. In SVCs and 3T3-L1 adipocytes, AMPK activation by metformin or AICAR inhibited TGF-β1-induced fibrogenesis and expression of LOX, which was further confirmed by ectopic expression of AMPK WT and K45R mutant. Consistently, in vivo, knocking out AMPK increased fibrosis and collagen cross-linking. Our study showed that AMPK downregulation due to obesity increases TGF-β signaling and LOX expression, which enhances adipose fibrosis and collagen cross-linking. Thus, AMPK is a therapeutic target for ameliorating the obesity-induced fibrosis, improving metabolic health of adipose tissue.

Pain Management Unit, Flinders Medical Centre, Bedford Park, SA 5042, Australia *Corresponding author. Received April 23, 1996; revised version received December 31, 1996; accepted January 2, 1997.

Sustained release morphine formulations are now generally accepted as the formulations of choice in the treatment of severe cancer pain. Kapanol™/Kadian™ (Glaxo/Faulding), a new sustained release formulation consisting of polymer coated pellets in a capsule, has recently been shown to have a superior morphine release profile compared to the standard tablet, MS Contin. If fact, the release characteristics of morphine from Kapanol suggested the possibility that one oral dose of Kapanol per 24 hours could effectively treat severe cancer pain. Twenty four patients completed a randomised, double-blind, two period, crossover study comparing 24-hourly Kapanol to 12-hourly MS Contin. The morphine dose per 24 hours was identical for the two formulations and morphine pharmacokinetics were determined over 24 hours at steady state for each formulation (i.e. after 7 days). The Cmax, Cmin, AUC and fluctuations in plasma morphine concentrations were not significantly different between the two formulations (P > 0.05, repeated measures ANOVA). Kapanol had significantly longer Tmax values (P < 0.001) than MS Contin. These results indicate that one Kapanol dog per 24 hours should at least be as efficacious as 12 hourly MS Contin in die treatment of severe cancer pain from the pharmacokinetic perspective. Sustained release morphine formulations are now generally accepted as the formulations of choice in the treatment of severe cancer pain. Kapanol™/Kadian™ (Glaxo/Faulding), a new sustained release formulation consisting of polymer coated pellets in a capsule, has recently been shown to have a superior morphine release profile compared to the standard tablet, MS Contin. If fact, the release characteristics of morphine from Kapanol suggested the possibility that one oral dose of Kapanol per 24 hours could effectively treat severe cancer pain. Twenty four patients completed a randomised, double-blind, two period, crossover study comparing 24-hourly Kapanol to 12-hourly MS Contin. The morphine dose per 24 hours was identical for the two formulations and morphine pharmacokinetics were determined over 24 hours at steady state for each formulation (i.e. after 7 days). The Cmax, Cmin, AUC and fluctuations in plasma morphine concentrations were not significantly different between the two formulations (P > 0.05, repeated measures ANOVA). Kapanol had significantly longer Tmax values (P < 0.001) than MS Contin. These results indicate that one Kapanol dog per 24 hours should at least be as efficacious as 12 hourly MS Contin in die treatment of severe cancer pain from the pharmacokinetic perspective.

A double-blind multidose trial of the addition of ketamine (0-40 mg, i.m., 8 times per day) to intramuscular morphine therapy was undertaken in a 61-year-old man with chronic back pain related to osteoporosis who had received inadequate pain relief from anterior interbody fusion, dorsal column stimulation and morphine alone. The patient reported only mild side effects. Nausea, tiredness and well-being were not significantly influenced by the ketamine dose level. Visual analogue pain scores prior to each dose were not associated with the ketamine dose level, but pain scores 30 min after doses were significantly reduced in a dose-related manner. In addition, the amount of morphine used by the patient was significantly reduced as the ketamine dose increased. This patient experienced substantial benefit from the addition of ketamine to intramuscular morphine therapy.

Objective: To review current surgical procedures for the relief of acute and chronic pain.Conclusions: Recent advances in knowledge of pain transmission and pain modulation have resulted in a more conservative approach to surgical intervention for the relief of pain. Those techniques which are contemporarily accepted as efficacious are outlined.

The reproducibility in bioavailability of orally administered morphine (as a solution) under fed and fasted conditions was studied in 5 patients with chronic pain on three occasions over 1 yr (0, 6, and 12 mo). During each study period (i.e., 0, 6, and 12 mo), patients received the 50 mg oral dose both in the fasted state (10 hr since food) and immediately after a high fat content breakfast, in randomly determined sequence. Frequent blood samples were collected for 10 hr after the dose. There was no significant difference in the maximum blood morphine concentration (C(max)) or the time to C(max) among the three study periods or between the fed and fasted states. Bioavailability, as assessed by log(AUC), was significantly greater in the fed compared to the fasted state (P < .01) but did not differ over the three study periods (Two-factor analysis of variance). Intrapatient variability contributed 32% and 54% to total variation in log(AUC) under fed and fasted conditions, respectively.

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.

The influence of a high-fat meal on blood morphine concentrations after the administration of a morphine solution (50 mg dose) was studied in 12 patients with chronic pain. The oral morphine dose was administered in a total volume of 200 ml to patients either immediately after food intake or while in the fasting state. There was a 34% increase in the area under the curve (AUC) when morphine was administered immediately after food when compared with the fasting state (p less than 0.02). However, there was no significant difference between the maximum blood morphine concentration (Cmax) or the time to maximum concentration (tmax) between the two treatment regimens. The shape of the blood morphine concentration-time curve was consistently altered in the fed patients compared with patients who were in the fasting state, inasmuch as the blood morphine concentrations were maintained at a higher level from 240 to 600 minutes after the dose when the morphine was administered with food (p less than 0.02). It is suggested that morphine concentrations are maintained at higher levels, possibly resulting in more prolonged pain relief, when morphine is administered with food compared with the same dose administered to patients who are in the fasting state.

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 μg i.v.) was administered at the same time as the TTS-fentanyl systems (50–125 μg/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.

Australian and New Zealand Journal of SurgeryVolume 59, Issue 4 p. 307-315 TREATMENT OF CANCER PAIN WITH ORALLY AND SPINALLY ADMINISTERED OPIOIDS MichaelJ. Cousins, Corresponding Author MichaelJ. Cousins Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia MB, BS, MD, FFARACS, FFARCS. *Recipient of the John Mitchell Crouch Fellowship, Royal Australasian College of Surgeons 1981.Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, SA 5042. Australia.Search for more papers by this authorGeoffreyK. Gourlay, GeoffreyK. Gourlay Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia BPHARM. PHD.Search for more papers by this authorDavidA. Cherry, DavidA. Cherry Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia MB, BS, FFARACS.Search for more papers by this authorJohnL. Plummer, JohnL. Plummer Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia BPHARM. PHD.Search for more papers by this author MichaelJ. Cousins, Corresponding Author MichaelJ. Cousins Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia MB, BS, MD, FFARACS, FFARCS. *Recipient of the John Mitchell Crouch Fellowship, Royal Australasian College of Surgeons 1981.Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, SA 5042. Australia.Search for more papers by this authorGeoffreyK. Gourlay, GeoffreyK. Gourlay Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia BPHARM. PHD.Search for more papers by this authorDavidA. Cherry, DavidA. Cherry Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia MB, BS, FFARACS.Search for more papers by this authorJohnL. Plummer, JohnL. Plummer Pain Management Unit, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia BPHARM. PHD.Search for more papers by this author First published: April 1989 https://doi.org/10.1111/j.1445-2197.1989.tb01572.xCitations: 1 *Recipient of the John Mitchell Crouch Fellowship, Royal Australasian College of Surgeons 1981. MB, BS, MD, FFARACS, FFARCS. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume59, Issue4April 1989Pages 307-315 RelatedInformation

Received from the Pain Management Unit, Department of An aesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia. Address correspondence to Dr. Sullivan, 1000 16th Street, Bellingham, WA 98225. Accepted for publication February 2, 1987.