Mental disorder prevalence in chronic pain patients using opioid versus non-opioid analgesics: A registry-linkage study.

BACKGROUND: Chronic pain and mental disorders are leading causes of disability worldwide. Individuals with chronic pain are more likely to experience mental disorders compared to individuals without chronic pain, but large-scale estimates are lacking. We aimed to calculate overall prevalence of mental health diagnoses from primary and secondary care among individuals treated for chronic pain in 2019 and to compare prevalence among chronic pain patients receiving opioid versus non-opioid analgesics, according to age and gender. METHODS: It is a population-based cohort study. Linked data from nationwide health registers on dispensed drugs and diagnoses from primary (ICPC-2) and secondary (ICD-10) health care. Chronic pain patients were identified as all patients over 18 years of age filling at least one prescription of an analgesic reimbursed for non-malignant chronic pain in both 2018 and 2019 (N = 139,434, 69.3% women). RESULTS: Prevalence of any mental health diagnosis was 35.6% (95% confidence interval: 35.4%-35.9%) when sleep diagnoses were included and 29.0% (28.8%-29.3%) when excluded. The most prevalent diagnostic categories were sleep disorders (14% [13.8%-14.2%]), depressive and related disorders (10.1% [9.9%-10.2%]) and phobia and other anxiety disorders (5.7% [5.5%-5.8%]). Prevalence of most diagnostic categories was higher in the group using opioids compared to non-opioids. The group with the highest overall prevalence was young women (18-44 years) using opioids (50.1% [47.2%-53.0%]). CONCLUSIONS: Mental health diagnoses are common in chronic pain patients receiving analgesics, particularly among young individuals and opioid users. The combination of opioid use and high psychiatric comorbidity suggests that prescribers should attend to mental health in addition to somatic pain. SIGNIFICANCE: This large-scale study with nation-wide registry data supports previous findings of high psychiatric burden in chronic pain patients. Opioid users had significantly higher prevalence of mental health diagnoses, regardless of age and gender compared to users of non-opioid analgesics. Opioid users with chronic pain therefore stand out as a particularly vulnerable group and should be followed up closely by their physician to ensure they receive sufficient care for both their mental and somatic symptoms.

Development and course of chronic pain over 4 years in the general population: The HUNT pain study.

BACKGROUND: Epidemiological studies of chronic pain frequently report high prevalence estimates. However, there is little information about the development and natural course of chronic pain. METHODS: We followed a random sample of participants from a population-based study (HUNT 3) with annual measures over 4 years. RESULTS: Among those without chronic pain at baseline, the probability of developing moderate to severe chronic pain (cumulative incidence) during the first year was 5%, a pain status that was maintained among 38% at the second follow-up. The probability of developing chronic pain diminished substantially for those who maintained a status of no chronic pain over several years. Subjects with moderate to severe chronic pain at baseline had an 8% probability of recovery into no chronic pain, a status that was maintained for 52% on the second follow-up. The probability of recovery diminished substantially as a status of chronic pain was prolonged for several years. Pain severity, widespread pain, pain catastrophizing, depression and sleep were significant predictors of future moderate to severe chronic pain, both among subjects with and without chronic pain at baseline. CONCLUSION: These findings suggest that the prognosis is fairly good after a new onset of chronic pain. When the pain has lasted for several years, the prognosis becomes poor. The same social and psychological factors predict new onset and the prognosis of chronic pain. SIGNIFICANCE: The development and recovery of chronic pain is highly dependent on previous pain. The prognosis of chronic pain may be predicted well when considering its duration in combination with other clinical, social and psychological factors. Targeting modifiable prognostic factors may be particularly important for newly developed chronic pain.

The duration and course of opioid therapy in patients with chronic non-malignant pain.

BACKGROUND: Prescription databases provide the opportunity for investigating opioid treatment and co-medication within large populations. So far, few studies have investigated the duration of opioid therapy, and large differences in discontinuation rates have been reported. METHODS: Data from the Norwegian Prescription Database were used to follow the study population of all adult persistent opioid users with non-malignant pain in Norway in 2005 (n = 44,867) for 6 years. Persistent opioid use was defined as being dispensed ≥ 180 defined daily doses (DDD) or 4500 mg oral morphine equivalents (OMEQ) during a 365-day period. The study population was stratified according to previous opioid use into new persistent opioid users, without previous persistent opioid use, and previous low-dose or previous high-dose persistent opioid users, having earlier persistent opioid use and received less or more than 120 mg OMEQ/day in 2005, respectively. RESULTS: Twenty-seven percent of new, 59% of previous low-dose, and 55% of previous high-dose users met the criteria of persistent use of opioids each year. Exactly, 22%, 11%, and 3% increased their cumulative yearly opioid dose by 200% or more during the study period. With 80% still being regular users of either drugs, 6 years later, long-term persistent opioid users were more likely to continue concomitant use of benzodiazepines or z-hypnotics than other users, CONCLUSION: The findings confirm high discontinuation rates in patients receiving opioids for chronic non-malignant pain. However, a clinically significant number of patients increase their doses over 6 years and many patients combine long-term opioid treatment with benzodiazepines and z-hypnotics.

Consumption of and satisfaction with health care among opioid users with chronic non-malignant pain.

BACKGROUND: Although persons with chronic pain are frequent users of the health care system, they report poor satisfaction with health care services. Participants with persistent opioid use in Nord-Trøndelag Health Study (HUNT)3 report severe pain in spite of treatment. The aim of the study was to test the hypothesis that subjects with persistent opioid use have both a higher consumption of health care services and a poorer satisfaction than the remaining subjects reporting chronic pain. METHODS: This cross-sectional study was based on linkage of self-reported data from the substudy (10,238 were invited, 6927 met the inclusion criteria) of health care use in HUNT3; a population-based health survey during the years 2006-2008 and the complete national registers of the Norwegian Prescription Database and the Cancer Registry of Norway. Patients with chronic pain are stratified according to the level of opioid use as persistent users of opioids, intermittent users, and persons not using opioids. RESULTS: Persons with chronic non-malignant pain reported a higher consumption of all health care services compared to the control group. Consumption of health care services increased with increasing level of opioid use. Persons with persistent opioid use were highly satisfied with all health care services, although less satisfied than persons without chronic pain. CONCLUSIONS: Combined with previous findings of high levels of pain in spite of opioid treatment, the present findings indicate that symptomatic relief is not a prerequisite for patient satisfaction. The study shows higher patient satisfaction compared to previous studies.

Reward responsiveness in patients with chronic pain.

BACKGROUND: It is proposed that changes in reward processing in the brain are involved in the pathophysiology of pain based on experimental studies. The first aim of the present study was to investigate if reward drive and/or reward responsiveness was altered in patients with chronic pain (PCP) compared to controls matched for education, age and sex. The second aim was to investigate the relationship between reward processing and nucleus accumbens volume in PCP and controls. Nucleus accumbens is central in reward processing and its structure has been shown to be affected by chronic pain conditions in previous studies. METHODS: Reward drive and responsiveness were assessed with the Behavioral Inhibition Scale/Behavioral Activation Scale, and nucleus accumbens volumes obtained from T1-weighted brain MRIs obtained at 3T in 19 PCP of heterogeneous aetiologies and 20 age-, sex- and education-matched healthy controls. Anhedonia was assessed with Beck's Depression Inventory II. RESULTS: The PCP group had significantly reduced scores on the reward responsiveness, but not reward drive. There was a trend towards smaller nucleus accumbens volume in the PCP compared to control group. There was a significant positive partial correlation between reward responsiveness and nucleus accumbens volume in the PCP group adjusted for anhedonia, which was significantly different from the same relationship in the control group. CONCLUSIONS: Reward responsiveness is reduced in chronic pain patients of heterogeneous aetiology, and this reduction was associated with nucleus accumbens volume. Reduced reward responsiveness could be a marker of chronic pain vulnerability, and may indicate reduced opioid function.

Use of prescribed opioids by children and adolescents: Differences between Denmark, Norway and Sweden.

BACKGROUND: There are few studies on the use of opioids among children and adolescents. The aim of this study was to determine the 1-year prevalence of prescribed opioid dispensing in Denmark, Norway and Sweden, and to compare gender and age differences in the use of weak and strong opioids between the three countries. METHODS: Data on the dispensing of opioids were collected from the websites of the complete national prescription databases in the three countries. All individuals aged 0-19 with at least one prescription of opioids during the study period were included. RESULTS: The 1-year prevalence of opioid use among young individuals aged 0-19 years increased during the study period (2006-2012) in Denmark from 2.5 to 3.4 per thousand, in Norway from 10.7 to 13.4 per thousand and in Sweden from 5.9 to 7.1 per thousand. In all three countries, more boys than girls used opioids between the ages of 0 and 10, whereas girls were the major users in the age range 11-19. Use of opioids in all three countries was dominated by weak opioids, codeine being the most dominant in Norway and Sweden and tramadol in Denmark. CONCLUSIONS: The 1-year prevalence of prescribed opioid use among children and adolescents in Norway was far higher than in Denmark and Sweden. During the study period, an increasing use of opioids among children and adolescents was observed in all three countries.

Long- or short-acting opioids for chronic non-malignant pain? A qualitative systematic review.

In selected patients with chronic non-malignant pain, chronic opioid therapy is indicated. Published guidelines recommend long-acting over short-acting opioids in these patients. The aim of this systematic review was to investigate whether long-acting opioids in chronic non-malignant pain are superior to short-acting opioids in pain relief, physical function, sleep quality, quality of life or adverse events. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for relevant trials up to July 2012. Reference lists of included trials and relevant reviews were in addition searched by hand. Of the 1168 identified publications, 6 randomised trials evaluating efficacy and safety filled the criteria for inclusion. None of them found a significantly better pain relief, significantly less consumption of rescue analgesia, improved quality of sleep or improved physical function from long-acting opioids. None of the trials investigated quality of life. None of the trials investigated adverse events properly nor addiction, tolerance or hyperalgesia. Three trials in healthy volunteers with a recreational drug use, found no difference in abuse potential between long- and short-acting opioids. While long term, comparative data are lacking, there is fair evidence from short-term trials that long-acting opioids provide equal pain relief compared with short-acting opioids. Contrary to several guidelines, there is no evidence supporting long-acting opioids superiority to short-acting ones in improving functional outcomes, reducing side effects or addiction.

Co-morbidity in persistent opioid users with chronic non-malignant pain in Norway.

BACKGROUND: In patients with chronic non-malignant pain (CNMP), co-morbid physical or mental health disorders are common and may have a negative impact on health-related quality of life and treatment outcomes. The purpose of this study was to examine the occurrence of chronic psychiatric and somatic diseases in persistent opioid users with CNMP compared with the general population in Norway. METHODS: In this cross-sectional study, prescription patterns of dispensed opioids were used to identify a study population of persistent opioid users with CNMP from the general population. Reimbursed prescriptions marked with diagnostic codes were used to identify the occurrence of 21 somatic and 3 psychiatric diseases for a 1-year period in the Norwegian Prescription Database. Occurrence of disease in persistent opioid users was compared to an age- and gender-specific population of all Norwegian residents aged 18-79 years in 2009. Standardized morbidity ratios (SMRs) for each disease were calculated. RESULTS: Eighty-five percent of the persistent opioid user population had at least one co-morbid disease compared with 45% of the general population. Forty-two percent had three or more co-morbidities. SMRs in both men and women were generally increased except for dementia, glaucoma and renal disease, indicating a higher occurrence of disease in persistent opioid users. CONCLUSIONS: A higher occurrence of both somatic and psychiatric co-morbidities in disease stages warranting pharmacological treatment was found in persistent opioid users with CNMP compared with the general population of Norway.

Concomitant medication among persistent opioid users with chronic non-malignant pain.

BACKGROUND: Recent guidelines for opioid treatment of chronic non-malignant pain discourage co-medication with benzodiazepines and benzodiazepine-related hypnotics, whereas co-medication with non-opioid analgesics and co-analgesics may offer a beneficial opioid sparing effect, and is recommended. The aim of this study was to describe 1-year periodic prevalence of co-medication with benzodiazepines, benzodiazepine-related hypnotics, non-opioid analgesics, co-analgesics and antidepressants in persistent opioid users with chronic non-malignant pain. METHODS: The study is based on data from the Norwegian Prescription Database, covering all drugs dispensed to outpatients in 2008. Concomitant medication levels were compared between users in two definitions of persistent opioid use, all Norwegian adults dispensed opioids in 2008 and the Norwegian background population. RESULTS: Of the Norwegian adult population studied, 1.2% met the criteria of persistent opioid use based on prescription pattern and prescription level. Sixty percent of persistent opioid users were dispensed a benzodiazepine or benzodiazepine-related hypnotic in amounts indicating regular use, with 15% dispensed a high amount of both classes. Sixty-two percent of persistent opioid users were dispensed one or more non-opioid analgesics, 47% an antidepressant and 33% were dispensed an antiepileptic drug. CONCLUSION: Approximately 60% of persistent opioid users also receive benzodiazepines or benzodiazepine-related hypnotics in amounts indicating regular use. This is in conflict with recent guidelines for the treatment of chronic non-malignant pain and may indicate that these users are at an increased risk of developing problematic opioid use.

Differential patterns of opioid use: defining persistent opioid use in a prescription database.

AIM: The aim of this study was to develop definitions to identify persons with clinically different patterns of persistent opioid use based on data from prescription databases. METHODS: The study is based on data from the Norwegian Prescription Database using all dispensed opioid prescriptions during 2005-2008. Three definitions of persistent opioid use were developed using the following patient criteria: different levels of dispensed opioid amounts, number of prescriptions and the number of quarters out of the year in which prescriptions were dispensed. The three definitions each have some typical patient characteristics attached to them. The strict definition describes a typical patient using opioids to achieve a continuous serum concentration in the therapeutic range, the intermediate definition represents a typical patient using opioids daily but not around the clock and the wide definition describes a typical patient who uses opioids most of the days. To study whether the definitions accurately represent long-term use, the patient population was followed for 3 years, and the retention rate within each definition was measured. RESULTS: The point prevalence of persistent opioid use in Norway (4,681,134 inhabitants) as defined by the strict, intermediate and wide definitions was 0.16% (n = 7663), 0.50% (n = 23,498) and 1.08% (n = 50,791), respectively, as of 31 December 2007. At the end of the 3-year study period, the retention within any of the definitions was 83%, 84% and 68% for patients who met the criteria of the strict, intermediate and wide definitions, respectively. CONCLUSION: In the patient populations identified by the three definitions, a high rate of retention was observed, indicating that the proposed definitions can identify patients with long-term persistent use of opioids.

Low-dose transdermal buprenorphine - long-term use and co-medication with other potentially addictive drugs.

INTRODUCTION: Recently, low-dose transdermal buprenorphine (LD-TD-BUP) was introduced for treatment of patients with chronic non-malignant pain. The primary aim of this study was to determine the proportion of patients who were prescribed LD-TD-BUP for non-malignant pain who became long-term users. The secondary aim was to determine the proportion of patients who co-medicated with other opioids or benzodiazepines during treatment with LD-TD-BUP. METHODS: Data were drawn from the Norwegian Prescription Database that covers all prescriptions dispensed at pharmacies to the entire Norwegian population (4.7 million inhabitants). The study population consisted of all patients who were dispensed at least one prescription of LD-TD-BUP from its introduction in November 2005 to 31 December 2008. Patients who were dispensed more than 24 patches (≥ 6 months) were defined as long-term users. Reimbursement codes were used to stratify patients as having cancer pain or non-malignant pain. RESULTS: Among new users of LD-TD-BUP for non-malignant pain (n = 13,451), only 22% became long-term users, while 44% were only dispensed one prescription. Among long-term users who were opioid naive when LD-TD-BUP was initiated, 43% co-medicated with other opioids or benzodiazepines, compared with 82% of those who previously had used opioids. CONCLUSION: Three years after introduction, 0.4% of the Norwegian population had been dispensed LD-TD-BUP. Only one-fifth had become long-term users. Those who used opioids before the first dispension of LD-TD-BUP co-medicated with other potentially addictive drugs to a much higher degree compared with those who were opioid naive.

Patients with problematic opioid use can be weaned from codeine without pain escalation.

BACKGROUND: Brief treatments for chronic non-malignant pain patients with problematic opioid use are warranted. The aims of the present study were to investigate (1) whether it is possible to withdraw codeine use in such patients with a brief cognitive-behavioural therapy (CBT), (2) whether this could be done without pain escalation and reduction in quality of life and (3) to explore the effects of codeine reduction on neurocognitive functioning. METHODS: Eleven patients using codeine daily corresponding to 40-100 mg morphine were included. Two specifically trained physicians treated the patients with six CBT sessions, tapering codeine gradually within 8 weeks. Codeine use, pain intensity, quality of life and neuropsychological functioning were assessed at pre-treatment to the 3-month follow-up. RESULTS: Codeine use was significantly reduced from mean 237 mg [standard deviation (SD) 65] pre-treatment to 45 mg (SD 66) post-treatment and to 48 mg (SD 65) at follow-up without significant pain escalation or reductions in quality of life. Moreover, neuropsychological functioning improved significantly on some tests, while others remained unchanged. CONCLUSION: The promising findings of codeine reduction in this weaning therapy programme for pain patients with problematic opioid use should be further evaluated in a larger randomized control trial comparing this brief CBT with both another brief treatment and attention placebo condition.

Prescription pattern of codeine for non-malignant pain: a pharmacoepidemiological study from the Norwegian Prescription Database.

BACKGROUND: Opioid prescription for pain relief is increasing. Codeine is the dominating opioid in several European countries, with Norway being among the highest codeine users. AIM: To determine whether codeine is primarily used for acute pain or whether there is a prescription pattern indicating problematic opioid use. METHODS: All pharmacies in Norway are obliged to submit data electronically to the Norwegian Prescription Database at the Norwegian Institute of Public Health on all dispensed prescriptions. Because all prescriptions are identified with a unique person identifier, it is possible to identify all prescriptions to one subject. All subjects who had prescription(s) of codeine dispensed to them in 2004, 2005 or 2006 are included in the study. RESULTS: 385 190 Norwegian persons had at least one prescription of codeine dispensed to them due to non-cancer pain in 2005, corresponding to a 1-year periodic prevalence of 8.3%. 223 778 (58%) received only one prescription in 2005, 121 025 (31%) received more than one prescription but <120 defined daily doses (DDDs), 30 939 (8%) received between 120 and 365 DDDs, 7661 (2%) between 365 and 730 DDDs, while only 1787 (0.5%) exceeded the maximum recommended dose of 730 DDDs. In the latter group, co-medication with benzodiazepines (65%) and carisoprodol (45%) was prevalent. CONCLUSION: About one in 10 adult persons in Norway were dispensed codeine in 2005. A majority (58%) received codeine only once, most likely for acute pain, whereas a small minority (0.5%) had a prescription pattern indicating problematic opioid use.

A controlled comparison between single doses of intravenous and intramuscular morphine with respect to analgesic effects and patient safety.

UNLABELLED: BACKGROUND AND AIM OF INVESTIGATION: Intramuscular (IM) administration has been considered to be safer than intravenous (IV) for opioids on wards, but a comparative knowledge of patient safety and analgesic potency following a single dose of IV and IM administration is lacking. This study was carried out to compare patient safety and analgesic efficacy of a single and high dose of morphine given IM or IV for post-operative pain management. MATERIALS AND METHODS: Thirty-eight patients with post-operative pain following hip replacement surgery were given IM or IV morphine 10 mg at a specified pain level. The study was randomized and double blinded. Time to onset of analgesic effect (11-point numeric rating scale), respiratory function (p(a)CO2, p(a)O2, and respiratory rate), level of sedation (5-point verbal rating scale), and hemodynamic function were recorded. RESULTS: In the IV group there was a slight but significant increase in p(a)CO2 after 5, 10, and 15 min compared with the IM group (5.2 vs. 4.8, 5.4, vs. 5.0 and 5.5 vs. 5.1 kPa, respectively). The IV group had a significantly faster onset of analgesic effect than the IM group (5 vs. 20 min). Between 5 and 25 min after morphine administration, pain status in the IV group was significantly improved compared with the IM group. Patients in the IV group were slightly more sedated than the IM group 5 and 10 min after morphine. CONCLUSION: A 10 mg bolus dose of IV morphine given to patients with moderate pain after surgery does not cause severe respiratory depression, but provides more rapid and better initial analgesia than 10 mg given IM. IV morphine even at a dose as high as 10 mg IV is well tolerated if there is a certain level of pain at its administration. The safety of IV morphine on the general ward needs to be further explored in adequately controlled studies.

Assessment of pain.

UNLABELLED: Valid and reliable assessment of pain is essential for both clinical trials and effective pain management. The nature of pain makes objective measurement impossible. Acute pain can be reliably assessed, both at rest (important for comfort) and during movement (important for function and risk of postoperative complications), with one-dimensional tools such as numeric rating scales or visual analogue scales. Both these are more powerful in detecting changes in pain intensity than a verbal categorical rating scale. In acute pain trials, assessment of baseline pain must ensure sufficient pain intensity for the trial to detect meaningful treatment effects. Chronic pain assessment and its impact on physical, emotional, and social functions require multidimensional qualitative tools and health-related quality of life instruments. Several disease- and patient-specific functional scales are useful, such as the Western Ontario and MacMaster Universities for osteoarthritis, and several neuropathic pain screening tools. The Initiative on METHODS: Measurement, and Pain Assessment in Clinical Trials recommendations for outcome measurements of chronic pain trials are also useful for routine assessment. Cancer pain assessment is complicated by a number of other bodily and mental symptoms such as fatigue and depression, all affecting quality of life. It is noteworthy that quality of life reported by chronic pain patients can be as much affected as that of terminal cancer patients. Any assessment of pain must take into account other factors, such as cognitive impairment or dementia, and assessment tools validated in the specific patient groups being studied.

Clinical pharmacology of methadone for pain.

BACKGROUND: This topical review addresses methadone's pharmacology, its application in malignant and non-malignant pain conditions, practical issues related to methadone for the treatment of pain and its influence on QTc time. METHODS: Relevant papers were identified in PubMed and EMBASE. RESULTS: Methadone is advocated by experts as a second line opioid when first line opioids fail to provide a satisfactory balance between pain control and side effects (opioid switching). Although randomized-controlled studies are lacking, current evidence suggests that switching to methadone in this situation reduces pain intensity. However, interindividual variability in its pharmacokinetics make its application challenging and metabolism by CYP 3A4 and 2B6 implies a substantial risk of drug-drug interactions. Several ways of switching to methadone have been presented, with a gradual switch during 3 days or 'stop and go' as the dominating strategies. Episodes of torsade de pointes arrhythmia during methadone treatment have been reported in patients with other risk factors for arrhythmia, while small prospective studies have reported a small, lasting and stable increase in QTc time. The extensive use of methadone for opioid replacement in addicts has added additional patient barriers to its use for pain control. CONCLUSION: In spite of challenges related to the variable pharmacokinetics and concerns regarding increase in QTc time, current evidence indicates that opioid switching to methadone improves pain control in a substantial proportion of patients who are candidates for opioid switching. Measures must be instituted to secure that patients receiving methadone for pain are not considered opioid addicts.

Chronic non-malignant pain patients report as poor health-related quality of life as palliative cancer patients.

BACKGROUND: Patients with chronic non-malignant pain (CNMP) conditions are known to report reduced health-related quality of life (HRQoL). The objective of this exploratory study was to compare HRQoL between patients admitted to a multidisciplinary pain centre, palliative cancer (PC) patients and national norms. METHODS: HRQoL data from 288 patients with CNMP admitted to the multidisciplinary pain centre at Trondheim University Hospital were compared with 434 patients with advanced cancer included in a trial of comprehensive palliative care in the hospital palliative medicine unit and national norms. HRQoL was assessed using the EORTC QLQ-C30. Age- and gender-adjusted norm data were calculated and compared between the two groups. RESULTS: Scores from both groups deviated from adjusted norm data on all scales, with poorer functioning and more symptoms. Compared with PC patients, CNMP patients reported a larger deviation (worse scores) on global quality of life, cognitive functioning, pain, sleep disturbances and financial difficulties. Deviations from norm data were similar for physical, social and emotional functioning, diarrhoea, dyspnoea and fatigue. PC patients reported worse scores on role functioning, nausea/vomiting, loss of appetite and constipation. CONCLUSION: CNMP patients admitted to multidisciplinary pain centres report significantly reduced HRQoL, in addition to severe pain. They consider their HRQoL to be as poor as HRQoL reported from dying cancer patients and substantially poorer than national norms. Factors other than the biological severity of the disease seem to be of major importance for self-reported HRQoL.

Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery.

AIM: To compare the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after intravenous and intramuscular administration after surgery. METHODS: This was a randomized double-blind, double-dummy study in patients who had undergone hip replacement surgery. Morphine (M, 10 mg) was administered intravenously (IV) or intramuscularly (IM). Arterial blood and CSF samples (from a spinal catheter) were drawn simultaneously at 10, 30, 60, and 120 min after administration. Morphine and metabolites [morphine-3-glucuronide (M-3-G), morphine-6-glucuronide (M-6-G), and normorphine (NM)] were determined by a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Thirty-eight patients were included: 13 men and 25 women, 20 in the IV, 18 in the IM group. Serum concentrations of M after 10 min were consistently higher after IM than IV, concentrations of M-3-G and M-6-G after IM surpassed those of IV after 45 min. NM was not found. None of the metabolites was found in CSF. CSF morphine concentrations and CSF/serum concentration ratios were consistently higher after IV compared to IM. The mean AUC(CSF)/AUC(serum) (0-120 min) concentration ratios were 0.18 and 0.09 after IV and IM, respectively. CONCLUSIONS: The uptake of morphine to the CSF was consistently higher after IV administration than after IM already after 10 min. The higher CSF concentration may be caused by an initially higher morphine blood/CSF gradient following IV morphine injection. The pharmacokinetic findings are compatible with a more rapid and extensive initial effect of IV morphine compared with IM.

Genetic variability and clinical efficacy of morphine.

The individual variability of opioid pharmacology suggests that the patients' genetic disposition influences the response to opioids. Given the complexity of morphine pharmacology, variability may be caused by several genes. We review data which shows that variability in genes coding the enzyme metabolizing morphine (UGT2B7 gene), mu-opioid receptors (OPRM gene) and blood-brain barrier (BBB) transport of morphine by multidrug resistance transporters (MDR1 gene) influences the clinical efficacy of morphine. Furthermore, variability in an enzyme degrading catecholamines (COMT gene) alters the efficacy of morphine demonstrating that genetic variability in non-opioid systems may indirectly influence the clinical efficacy from morphine. Thus, results obtained so far strongly argue that opioid efficacy is partly related to inborn properties caused by genetic variability.