Methadone for the management of pain in advanced cancer

Abstract

Most patients at advanced stages of cancer experience moderate to severe pain [1, 2]. Despite increased research and attempts on estimation and management, pain continues to be a predominant symptom in patients with cancer [1]. In general, cancer pain is treated with pharmacological agents, specifically using opioids alone or in combination with adjuvant analgesics [3]. Methadone is administered to patients with cancer pain not responsive to morphine or other strong opioids when intractable opioid adverse effects appear [4]. The inherent properties of methadone, including high oral bioavailability, rapid onset of analgesic effect, long half-life resulting in infrequent dosing regimens, lack of active metabolites, low rate of induction of tolerance, low cost, and perceived benefit in difficult pain control scenarios such as neuropathic pain, facilitates its use in in the management of pain in profoundly ill patients [5, 6]. Methadone is also considered as the first strong opioid analgesic in patients with renal impairment [4]. However, in clinical practice the use of methadone is highly restricted due to the narrow therapeutic window between efficacy and toxicity accompanied with large inter- and intra-individual variability in response [2]. Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of methadone could help determine appropriate opioid selection for individual patients with advanced cancer. In clinical practice, methadone is administered as a racemic mixture of l-and d-methadone and the analgesic properties are mostly attributed to the l-enantiomer. Clinical studies have also indicated the disposition of methadone to be enantioselective [7-9]. Evaluation of the PK profile of the methadone enantiomers requires accurate quantitation of each enantiomer. The use of saliva as a surrogate to plasma samples has been evidenced by strong correlations reported for analgesics such as paracetamol [10] and hydromorphone [11], with mixed results for methadone [12-14]. Saliva sampling would prove to be useful in drug monitoring and PK studies, especially in patients with advanced cancer where ethical and medical reasons limit invasive procedures on this patient population with their persistent declining health condition. Quantitation of l- and d-methadone in biological samples requires an accurate, sensitive and robust analytical method. Unfortunately, the complex matrices used in the bioanalysis can cause interference, requiring estimation and minimisation of these effects to ensure accuracy and precision of results, especially when they are applied in PK studies [15]. An integrated population PK study of methadone enantiomers using NONMEM, provides a powerful and flexible means of obtaining estimates of both the inter- and intra-individual variability in PK parameters and identifies factors (covariates), such as patient characteristics, that influence the PK behaviour of the drug and thus explain some of the inter-individual variability of methadone response. Further, investigation of the pharmacogenetic factors, such as genetic polymorphisms of the enzymes involved in PK characteristics and drug transporters/ receptors in PD aspects of methadone, may provide insight into the variability in efficacy and adverse events of methadone in clinical practice. This study commenced with an extensive review on suppression and enhancement of ionisation (SEI) which provided insight into the phenomenon of SEI in high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS), its minimisation and assessment. With heterogeneous sample matrices to be analysed, this review provided information on methods to assess and minimise the deleterious effect of SEI on the measured concentrations of the methadone enantiomers. In the next stage, a highly sensitive, accurate and precise analytical method to quantitate l-and d-methadone in total and unbound plasma and saliva samples was developed and validated over a wide concentration range of 0.05 - 1000 ng/mL, using HPLC-MS/MS. A simple one-step extraction process was designed for sample preparation for both plasma and saliva, in comparison to complex extraction procedures generally employed. This method successfully addressed the low saliva sample volume available due to xerostomia in patients with advanced cancer, and the potential loss of methadone by adsorption on to the saliva collection device (Salivette®), with extraction efficiencies of 96% and 97% (0.5 ng/mL), and 99% and 98% (500 ng/mL) for l- and d-methadone respectively. SEI was also investigated across a large number (n=60) of samples from different origins, with no presence of interference at the retention time of both l- and d-methadone, thus demonstrating accuracy in the quantitation of the enantiomers. In the third stage of this study, 151 paired plasma and saliva samples provided by 50 adult patients being cared for at the oncology and palliative care service of the Mater Adults Hospital and St. Vincent’s Private Hospital, Brisbane, were evaluated for possible relationships between l- and d-methadone plasma (total and unbound) and saliva concentrations. The concentration of methadone enantiomers was found to be higher in saliva samples, suggesting the possibility of active transport into saliva. Statistical analysis to evaluate correlation of plasma and saliva concentrations did not reveal any significant relationships. While the saliva/plasma (S/P) ratio of the concentration of methadone enantiomers was quite stable across the dosing range, variability in individual S/P ratios indicated that saliva may not serve as a surrogate for plasma in PK studies of methadone in patients with advanced cancer. In the fourth stage of this study, pharmacogenetic factors that could contribute to the inter-individual variability in response to methadone were investigated by examining the potential influence of several polymorphisms associated with the genes ABCB1, OPRM1, ARRB2, BDNF and KCNJ6. No significant associations were found between the genotypes and the methadone dose requirement or the therapeutic response, as measured by pain scores. In the final stage, the population PK characteristics of the methadone enantiomers were analysed using NONMEM for the plasma concentrations of l-and d-methadone. Patient specific factors (covariates) which influenced the PK and explained the variability in methadone response were identified with the future aim of supporting dose individualisation of methadone. Being an acute phase protein that is elevated in patients with advanced cancer [16], the concentration of α1-acid glycoprotein (AAG) was included in model building to improve predictive performance. A one-compartment model with first-order elimination described the data. The population PK parameters for this one-compartment model were 365 L and 279 L for volume of distribution for l-and d-methadone respectively, and clearance (CL) was 3.67 L/h/70 kg for both enantiomers. Since preliminary models resulted in very similar CL values for both enantiomers, CL was not estimated differently. Addition of weight of the patients as a covariate in model building resulted in a reduction in unexplained variability on CL from 71.4% to 66.7%. The AAG concentration in plasma was found to be significant and improved the predictive performance of the model. A multidisciplinary approach was used in this study to evaluate the PK/PD characteristics of methadone to explain the wide variability observed in therapeutic response in cancer populations. A highly sensitive, simple bioanalytical method to quantitate the enantiomers of methadone in plasma and saliva was developed, providing the basis for future PK/PD studies or for monitoring efficacy, toxicity and side effects. The prevalence of SEI in bioanalysis was reviewed with strategies provided to minimise the effect of SEI. Correlation analysis of plasma and saliva samples in the clinical study revealed higher saliva concentrations in comparison to plasma, which benefits sensitivity in instrumental analysis and showed the presence of an active transport system for the transfer of methadone into saliva. Pharmacogenetic analysis included studies on polymorphisms influencing the PK and PD characteristics of methadone in cancer patients when information on this patient population is sparse. With very limited information on population PK studies of methadone in cancer patients, this study described methadone population PK using plasma concentrations of l-and d-methadone, and identified patient specific factors that influenced the PK, with the future aim of supporting dose individualisation of methadone for pain management in patients with advanced cancer.