Tarja Heiskanen

Controlled-release oxycodone and morphine in cancer related pain

&NA; Controlled‐release (CR) formulations of oxycodone and morphine were compared in 45 patients with chronic cancer pain. The study was started with an open‐label, randomised titration phase to achieve stable pain control for at least 48 h, followed by a double‐blind, randomised, crossover phase in two periods, 3–6 days each. To blind the study using available tablet strengths, the dose ratio of oxycodone to morphine was set at 2:3. A daily telephone contact was maintained between the patient and the investigator. The patients were asked to assess pain intensity four times a day and acceptability of therapy twice daily, and to record possible adverse effects. Pharmacodynamic evaluations were performed at the end of each double‐blind period. The patients were allowed to use escape analgesic (respective opioid as oral solution) as needed. Twenty‐seven patients were evaluable for both safety and efficacy. Pain was well‐controlled during both stable phases. When the period effect was taken into account the two opioids provided comparable analgesia. If the results of the two periods were combined, the patients consumed significantly more escape doses and the mean pain intensities were significantly greater with CR oxycodone. The total opioid consumption ratio of oxycodone to morphine was 2:3 when oxycodone was administered first, and 3:4 when oxycodone was administered after morphine. The total incidence of adverse experiences reported by the patients was similar, but significantly more vomiting occurred with morphine, whereas constipation was more common with oxycodone.

Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.

Oxycodone is metabolized in the liver by means of O‐demethylation to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poor metabolizers). Several drugs are metabolized by CYP2D6, and clinically relevant drug interactions may occur. The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine.

Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics and mechanisms.

Breakthrough pain or transient worsening of pain in patients with an ongoing steady pain is a well known feature in cancer pain patients, but it is also seen in non‐malignant pain conditions with involvement of nerves, muscles, bones or viscera. Continuous and intermittent pain seems to be a general feature of these different pain conditions, and this raises the possibility of one or several common mechanisms underlying breakthrough pain in malignant and non‐malignant disorders. Although the mechanisms of spontaneous ongoing pain and intermittent flares of pain (BTP) may be difficult to separate, we suggest that peripheral and/or central sensitization (hyperexcitability) may play a major role in many causes of BTP. Mechanical stimuli (e.g. micro‐fractures) changes in chemical environments and release of tumour growth factors may initiate sensitization both peripherally and centrally. It is suggested that sensitization could be the common denominator of BTP in malignant and non‐malignant pain.

Epidural and subcutaneous morphine in the management of cancer pain: a double-blind cross-over study

&NA; Ten patients who suffered from severe cancer‐related pain participated in a randomised, double‐blind and cross‐over study to compare the effectiveness and acceptability of epidural and subcutaneous administration of morphine. The patients titrated themselves pain‐free in 48 h using a patient controlled analgesia system. The median daily doses calculated from the consumption of the last 4‐h study period were 372 mg for subcutaneous and 106 mg for epidural administration. The two modes of morphine administration turned out to be comparable in terms of both effectiveness and acceptability. Both treatments provided better pain relief with less adverse effects compared with the prestudy oral morphine treatment.

Transdermal fentanyl in cachectic cancer patients

ABSTRACT Fentanyl is an opioid with high lipid solubility, suitable for intravenous, spinal, transmucosal and transdermal administration. The transdermal fentanyl patch has become widely used in the treatment of both malignant and non‐malignant chronic pain. The absorption of fentanyl from the patch is governed by the surface area of the patch, by skin permeability and by local blood flow. The aim of this study is to find out whether absorption of fentanyl in cachectic patients with cancer‐related pain is different from that of normal weight cancer patients. We recruited ten normal weight (mean body mass index (BMI) 23 kg/m2) and ten cachectic (mean BMI 16 kg/m2) cancer pain patients. A transdermal fentanyl patch with a dose approximately equianalgesic to the patients’ previous opioid dose was administered to the upper arm of the patient for 3 days. Prior to patch application, the height, weight and BMI of the patient, as well as upper arm skin temperature, local sweating, thickness of skin fold and local blood flow were measured. Plasma fentanyl concentrations were analyzed from blood samples taken at baseline, 4, 24, 48 and 72 h. Plasma fentanyl concentrations adjusted to dose were significantly lower at 48 and 72 h in cachectic patients than normal weight patients. The cachectic patients had a significantly thinner upper arm skin fold, but no differences were found in local blood flow, sweating, or skin temperature. Absorption of transdermal fentanyl is impaired in cachectic patients compared with that of normal weight cancer pain patients.

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.

Multidisciplinary pain treatment – Which patients do benefit?

Abstract Background The prevalence of chronic non-malignant pain in developed countries is high, ranging from 14% to 50%. Patients with chronic pain are active users of health-care services and they report impaired health-related quality of life (HRQoL) when compared with the general population. Psychological distress has been identified as one of the risk factors for pain chronicity. Depression, anxiety and negative beliefs are associated with pain interference and perceived disability. Multidisciplinary pain management (MPM) aims to rehabilitating chronic pain patients by addressing both physical, psychological, social and occupational factors related to the pain problem. MPM programmes have been shown to be effective in reducing pain and improving function in patients with diverse chronic pain states. However, MPM programmes are often heterogeneous and predicting MPM treatment results in different patients groups may be difficult. Methods The present study examined changes in HRQoL after MPM in 439 patients treated at a multidisciplinary pain clinic using the 15D HRQoL questionnaire. The characteristics of the 100 patients with the greatest improvement and the 100 patients with the largest decrease in HRQoL were examined more closely (demographics, characteristics of pain, pain interference, psychiatric comorbidity, employment status, details of MPM) after answering a follow-up 15D questionnaire at three years after their MPM had ended. Result During MPM, HRQoL was significantly improved in 45.6% of the 439 patients, decreased in 30.7% of the patients and did not change in 23.7% of the patients. Patient-related factors that predicted a better HRQoL among the 100 patients with good MPM outcome compared with the 100 patients with poor MPM outcome were higher education and better employment status. Age, gender, marital status, duration of pain, number of pain sites, pain intensity or pain interference at baseline did not differ between the patient groups. Patient expectations regarding MPM were similar. A tendency towards more psychiatric comorbidity in the non-responder group was seen. The duration of MPM in the two patient groups was similar, as well as the number of medications started, the variety of specialists seen and psychiatric counselling with supportive therapy included. More non-responder than responder patients had died during the three-year follow-up period, some of the deaths were related to substance abuse. Conclusions and Implications HRQoL in chronic pain patients was significantly improved during MPM compared with the baseline. Pain duration of several years, multiple pain sites and neuropathic pain were not discerning factors between the responders and non-responders of the present study, implying that a positive change in HRQoL may be achieved by MPM even in these pain patients. In agreement with previous studies, factors predicting poor treatment outcome in the non-responder group of chronic pain patients were not treatment related. To further improve MPM outcome even in pain patients with risk factors for less benefit of treatment such as low education and poor general health, more individualized MPM approaches with emphasis on analysis and treatment of psychological symptoms and patient beliefs is essential.

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients

Abstract Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients. The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20 mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1. Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0–12h of oxycodone by 19% (−23 to 113%; P = 0.003), and that of noroxycodone by 100% (5–280%; P < 0.0001) but decreased the AUC0–12 h of oxymorphone by 67% (−100 to −22%; P < 0.0001) and that of noroxymorphone by 68% (−100 to −16%; P < 0.0001). Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P = 0.0471) indicating that these adverse effects were due to paroxetine. No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied. The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

Pharmacology of oxycodone: does it explain why oxycodone has become a bestselling strong opioid?

Abstract As morphine, oxycodone is a m-opioid receptor agonist with a significantly different pharmacokinetic profile compared with morphine. It seems that oxycodone is able to compensate its lower binding affinity for the m-opioid receptor compared with that of morphine by active transport to the central nervous system. Although the analgesic properties of oxycodone are mainly due to its own activity, cytochrome (CYP) inhibitors and inductors may change oxycodone-induced analgesia as a result of higher or lower, respectively, oxycodone concentrations.

Why does the impact of multidisciplinary pain management on quality of life differ so much between chronic pain patients

Abstract Aims To assess the change in quality of life and factors predicting this change in 1425 chronic pain patients treated in a multidisciplinary pain clinic. Methods This is an observational follow-up study using the 15D generic health-related quality of life (HRQoL) instrument. Patients filled in the HRQoL questionnaire at baseline, and 6 and 12 months after discharge. To assess if mental factors predicted treatment success, the changes in the overall 15D score were compared and related to the baseline variables of depression and distress. The group of patients, who scored 4 or 5 on the 1–5 scale for the depression and distress dimensions of the 15D instrument, were considered mentally distressed (N =199). They were compared with the non-distressed patients (i.e. those who scored 1; N = 401). Results Pain was associated to depression and distress: 85.4% of mentally distressed patients scored 4 or 5 also on the discomfort and symptoms dimension, vs. 51.4% of the non-distressed (p < 0.001). The mean 15D score of the mentally distressed patients improved statistically significantly more (from 0.572 to 0.636, N =141) during the first six months after treatment compared with the 15D of those who were not mentally distressed, who improved only marginally (0.790–0.803, N = 294; p < 0.001). Conclusions Patients with more severe depression or distress at baseline appear to gain more from the treatment than those who have less mental distress. In our ongoing study more baseline factors will be evaluated to assess their effect on the success of treatment.