Long-term outcome of multidisciplinary intervention of chronic non-cancer pain patients in a private setting.

Background and aim The present study reports on chronic non-cancer patients who were referred to a private pain clinic, according to a waiting time guarantee and treated within one month from referral. Based on evaluation by members of the multidisciplinary staff at our pain clinic a pain management program could be offered individually or as group therapy. Methods Health related quality of life, psychometric tests, use of pain medication; socio-economic status and number of consultations in general practice were recorded at referral to the clinic and by postal questionnaires at follow-up 21 months later. The primary treatment outcome (treatment success) was defined as an improvement of at least 40 points in the physical component and/or the mental component of SF-36 from baseline to follow-up. Secondary outcome measures were changes in Beck's Anxiety Inventory and Beck's Depression Inventory, use of analgesics, work status and transfer income and number of consultations at the GP's office due to the chronic pain condition. Results A total of 306 patients were included: 141 were treated individually and 165 were treated in groups. At follow-up, data were obtained from 189 patients (62%). Comparing baseline to follow-up data, 62% of group treated patients were treated successfully, compared with 41% of individually treated patients. Anxiety and depression were significantly improved in group treated patients but not in those treated individually. significantly more patients had work income (and less patients transfer income) among group treated, compared with individually treated. At follow-up use of antidepressants and anticonvulsants was increased whereas use of tranquilizers and strong opioids was decreased in all patients. Number of consultations at their GPs due to chronic pain was significantly reduced in all patients. Conclusions Multidisciplinary treatment in a private pain clinic seems to have a long-term effect in relation to biological, psychological and social aspects of the chronic pain condition. Treatments based on group therapy may offer better results than individual treatment courses. Implications The effect of group therapy should be explored further.

[Tapentadol is a new, strongly efficative analgeticum with dual effect mechanisms]. / Tapentadol er et nyt stærktvirkende analgetikum med to virkningsmekanismer.

Tapentadol exerts its analgesic effects through opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Clinical studies show that tapentadol effectively relieves moderate to severe pain in both post-operative and chronic pain. In these trials with equianalgesic doses of tapentadol and oxycodone, treatment with tapentadol was associated with significantly fewer gastrointestinal-related adverse events. Furthermore, in a placebo-controlled study, tapentadol has shown good efficacy in painful diabetic polyneuropathy.

A randomized, open, parallel group, multicenter trial to investigate analgesic efficacy and safety of a new transdermal fentanyl patch compared to standard opioid treatment in cancer pain.

A new 72-hour transdermal fentanyl matrix patch has been designed, which has a 35%-50% reduction of the absolute fentanyl content compared with other currently available transdermal fentanyl patches that are using the matrix technology. The new patch has previously been shown to be pharmacokinetically bioequivalent to the marketed fentanyl patch. To determine noninferiority in efficacy in cancer patients and to compare safety, a clinical trial comparing the new fentanyl patch with standard oral or transdermal opioid treatment was planned. The design was an open, parallel group, multicenter trial, in which 220 patients were randomized to receive either the fentanyl patch or standard opioid treatment for 30 days. The primary efficacy variable, pain intensity (PI) on a 0-10-point numerical rating scale, was recorded once daily. The primary endpoint was the relative area under the curve of PI expressed as a percentage of the maximum possible PI area under the curve. Any adverse events were recorded; four tolerability endpoints, constipation, nausea, daytime drowsiness, and sleeping disturbances, were assessed daily. Noninferiority was shown; the upper 95% confidence interval limits of the mean difference in relative PI area under the curve between the fentanyl patch and standard opioid treatment were less than 10% for both the intention-to-treat and per-protocol populations. Scores for the tolerability endpoints were similar in the treatment groups. The new fentanyl matrix patch with a lower drug load was found noninferior and as safe as established standard oral and transdermal opioid treatment.

What do different databases tell about the use of opioids in seven European countries in 2002?

OBJECTIVE: The objective of this paper was to analyse opioid consumption in a number European countries using different sources of data. METHODS: Data were extracted from the United Nations' International Narcotics Control Board Report (INCB) 2003 and from the registers of the national health authorities in seven countries where data were available for 2002. The amount of opioid used was calculated as daily defined doses per 1000 inhabitants per day (DDD/1000/day). Danish Register of Medicinal Products Statistics was further explored for characteristics of opioid consumption (age, gender, type of opioids consumed) by patients in primary care. Total opioid consumption and consumption of 11 selected opioids (7 strong and 4 weak) were analysed. The amount of opioids consumed by outpatients was also examined. RESULTS: There were considerable differences in the number of opioids reported and significant discrepancies in the amounts of opioids consumed between the national data and the INCB report. The source of data for the national registers on drug consumption varied (pharmacies or wholesale). The INCB data provide information on opioid import and estimated need rather than on medical consumption. CONCLUSIONS: Caution is required when interpreting the data on opioid consumption between countries because of differences in the collection and reporting of data. Better recording of opioid consumption is needed for meaningful analysis of opioid consumption and its possible effect on pain management in different countries. Data on opioids consumed for cancer-related pain in comparison with chronic non-malignant pain are needed. A uniform method of collection of data on analgesic consumption should be established for all European countries.

[Pain relief]. / Symptomlindring--smerter.

Pain in palliative patients demonstrates impact from many dimensions. This article focuses on pain and typical treatment problems in this respect. A pain analysis is mandatory before initiating pharmacological treatment. However, there are often problems with neuropathic and breakthrough pain. A special issue is the possible toxicity of opioids with acute tolerance and central nervous system sensitisation resulting in increased pain intensity. A key word in the treatment of opioid induced problems is opioid rotation. As pain is very dynamic, close monitoring is recommended.

Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers.

OBJECTIVE: The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. METHODS: Twenty-three healthy male volunteers aged 21-40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentration-time profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM: software. RESULTS: A three-compartment model best described the plasma concentration-time course. Body weight was found to be a significant covariate for elimination clearance in a linear fashion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V(1), 81.8%), peripheral distribution volume 1 (V(2), 23.7%) and inter-compartmental clearances between V(1) and V(2) (Q(2), 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. CONCLUSION: Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the mode of administration should be used in the design of dose regimens of buprenorphine.

Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers.

AIM: After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers. METHODS: The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively. RESULTS: The plasma concentration peaks of M6G were seen at 4.0 (2.0-6.0) and 18 (12.0-24.0) h after 200 mg M6G and at 3.5 (2.0-6.0) and 21.3 (10.0-23.3) h after 50 mg M6G, which was in agreement with previously published results. The K(M6G_abs)/K(M6G_M6G) ratio was found to be 10. CONCLUSION: The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K(M6G_abs)/K(M6G_M6G) ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.

[Differences in the prescription of analgesics in the treatment of cancer pain in six Danish pain treatment units]. / Forskelle på ordinationsmønstret af analgetika ved behandling af cancersmerter på seks danske smertebehandlingsenheder.

30-40% of cancer patients suffer from pain at diagnosis while 70-80% of patients at progressed stages of the disease suffer from pain. Background pain is treated with long-acting opioids. Breakthrough pain can be treated with shorter acting non-opioid analgesics or opioids. The aim of this study was to describe the medical treatment of pain in cancer patients in connection with six Danish hospital units with special expertise in pain treatment. Differences in the prescription of analgesics were studied. The study was performed as a cross section study of prescribed analgesics. Data was collected by reviewing medical records. The study included 347 patients. A total of 278 patients out of 347 were treated with opioids for background pains. A significant difference was found (P < 0.001) in the frequency of prescribing morphine, oxycodone and fentanyl. For the treatment of background pain secondary analgesics were prescribed for 40% of the patients while 50% of the patients were treated with paracetamol and/or NSAID. According to the medical records 79% of the patients were prescribed analgesics for breakthrough pain. 73% of the 347 patients had strong opioids prescribed for breakthrough pain. For the treatment of background pain opioids were prescribed for the majority of the cancer patients. Morphine and oxycodone were prescribed most frequently. Secondary analgesics and paracetamol and/or NSAID were also prescribed for background pain. The strong opioids were prescribed for the treatment of breakthrough pain. Differences in the prescription of analgesics between the six hospital units were observed in this study.

Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain.

BACKGROUND: In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled. METHODS: Assessments for pain, sedation and other morphine induced side effects were made several times for 19 cancer patients treated with changing doses of oral sustained release (SR) morphine and twice for 17 non-cancer patients treated with stable doses of SR morphine. Blood samples were obtained simultaneously and analysed for contents of morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC). RESULTS: Significant correlations were found between the daily dose of SR morphine and plasma morphine (r = 0.469, p < 0.01), plasma M-6-G (r = 0.677, p < 0.01), and plasma M-3-G ((r = 0.827, p < 0.01), in the cancer patient group, but only between the daily dose of SR morphine and plasma M-3-G (0.662, p < 0.01) and plasma M-6-G (0.571, p < 0.01) in the non-cancer patient group. Normalised M-3-G/M and M-6-G/M ratios for the cancer patient group were independent of duration of treatment and daily dose of SR morphine. Likewise in the non-cancer patient group duration of treatment did not influence the metabolite ratios. Correlations between pain score and plasma morphine, M-6-G and M-6-G/M were weak in the cancer patient as well as in the non-cancer patient group making it impossible to draw any conclusion regarding the potential contributory analgesic effect of M-6-G. Dryness of the mouth was the most frequent adverse effect reported in the non-cancer as well as the cancer patient group. In the latter group patients complaining of dryness of the mouth had significantly higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. This difference persisted (or was close to significance) when excluding patients receiving antidepressants. CONCLUSION: In the cancer patient group neither dose nor treatment period seems to influence morphine glucuronidation. Likewise in the non-cancer patient group receiving stable doses of morphine duration of treatment does not seem to influence morphine glucuronidation. Dryness of the mouth was positively correlated to high plasma concentrations of morphine and M-6-G.

A one year health economic model comparing transdermal fentanyl with sustained-release morphine in the treatment of chronic noncancer pain.

A Markov model was constructed to simulate the resource use and health outcomes of one year of treatment comparing the fentanyl transdermal therapeutic system (fentanyl-TTS) with oral sustained-release (SR) morphine in outpatients with noncancer pain in Denmark. Effectiveness was assessed in terms of days of good pain control and days on initial treatment. Costs included those of baseline pain management, including breakthrough pain; co-medication costs; and control of adverse events. Fentanyl-TTS was more effective than SR-morphine in achieving good pain control (99 vs. 64 days, respectively) and the incremental cost-effectiveness of fentanyl-TTS was US dollars 10.26 per extra day of good pain control. Patients treated with fentanyl-TTS remained considerably longer on initial treatment compared with those treated with SR-morphine (166 days vs. 117 days, respectively). The results of this study suggest that fentanyl-TTS is a competitive therapeutic and economic choice for the treatment of chronic noncancer pain.

Changing M3G/M6G ratios and pharmacodynamics in a cancer patient during long-term morphine treatment.

A cancer patient receiving long-term oral sustained-release morphine treatment and periodically presenting with unusually high plasma M3G/M6G ratios is described. We found the patient's formation of M6G more unstable and perhaps delayed compared to the formation of M3G. There is no apparent explanation for this phenomenon and the high M3G/M6G ratios had no implications for the patient's pain experience or side effects from the morphine treatment.

Management of cancer pain in Denmark: a nationwide questionnaire survey.

A questionnaire survey was carried out with the aim of evaluating knowledge about and practice of cancer pain treatment in Denmark. A questionnaire was sent out to a 10% random sample of Danish physicians. Of these 1411 physicians, 1068 (76%) returned the questionnaires and after exclusion of those doctors who never treated cancer patients, 577 (54%) were analyzed. Their knowledge of the principles and practice of cancer pain treatment was evaluated by means of 14 multiple-choice and open questions. Their ability to apply their knowledge in practice was evaluated by analyzing their suggested treatment of 3 simulated patient cases. The results show that a vast majority (97%) of the physicians were prepared to use opioids conventionally administered for severe pain and that 39% reported the use of other treatment modalities (psychological treatment, antineoplastic therapy, transcutaneous nerve stimulation/acupuncture, etc.). Ninety-seven percent of the physicians recognized difficulties in cancer pain treatment, the most frequent being side effects of drugs and inadequate pain relief. Seventy-five percent considered that their knowledge about pain treatment was fair or better. The overall evaluation of the proposals for pain treatment of the patient cases was primarily based on drug therapy. Adequate doses, correct dose intervals and selection of drugs, routes of administration and other treatments were the requirements for satisfactory answers. It appears that the majority the physicians could treat both pain from bone metastasis (75%) and visceral pain (78%) satisfactorily, while very few suggested co-analgesics for neuropathic pain conditions (20%). Older physicians performed less well than their younger colleagues. Basic pain treatment skills have been acquired by the Danish physicians but, in the future, emphasis should be placed on the treatment of neuropathic pain with co-analgesics and the management of opioid side effects.

Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists.

Hyperalgesia and allodynia in 4 cancer patients treated with morphine disappeared after discontinuing or substituting morphine with other opioid agonists. The first case describes a young female who developed hyperalgesia and myoclonus during intravenous morphine infusion. The hyperalgesia and myoclonus disappeared when the morphine administration was discontinued and she felt comfortable on small and sporadic oral doses of methadone. The second case describes hyperalgesia occurring after a small dose of sustained-release morphine which disappeared after alternative use of oral ketobemidone. The third case describes hyperalgesia following high doses of intramuscular morphine which disappeared after alternative use of continuous subcutaneous infusion of sufentanil. The fourth case describes a boy developing hyperalgesia after high doses of oral and intramuscular morphine. The hyperalgesia disappeared after discontinuing morphine administration but withdrawal symptoms developed due to too small doses of methadone. Possible mechanisms of morphine-induced hyperalgesia are discussed.

Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine.

Eight cancer patients in the terminal stages of the disease treated with high doses of intravenous morphine developed hyperalgesia. All cases were retrospectively sampled from three different hospitals in Copenhagen. Five patients developed universal hyperalgesia and hyperesthesia which in 2 cases were accompanied by myoclonus. In 3 patients a pre-existing neuralgia increased to excruciating intensity and in 2 of these cases myoclonus occurred simultaneously. Although only few clinical descriptions of the relationship between hyperalgesia/myoclonus and high doses of morphine are available, experimental support from animal studies indicates that morphine, or its metabolites, plays a causative role for the observed behavioural syndrome. The possible mechanisms are discussed and treatment proposals given suggesting the use of more efficacious opioids with less excitatory potency in these situations.