Switching From Morphine to Methadone to Improve Analgesia and Tolerability in Cancer Patients: A Prospective Study

Mercadante, Sebastiano; Casuccio, Alessandra; Fulfaro, Fabio; Groff, L; Boffi, Roberto; Villari, Patrizia; Gebbia, Vittorio; Ripamonti, Carla

doi:10.1200/jco.2001.19.11.2898

Cited by 235 publications

(196 citation statements)

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“…For opioid agents, the morphine equivalent daily dose (MEDD) was calculated based on established recommendations. 9 We categorized non-opioid medications that were prescribed into the following groups: (1) benzodiazepines, (2) antidepressants, (3) anticonvulsants, and (4) non-steroidal anti-inflammatory agents. The pain intensity was assessed using the Numerical Categorical Scale (0 to 10 points), with 0 indicating "no pain", 10 "maximum pain", whereas the other scores, from 2 to 9, indicated intermediary perceived pain levels.…”

Section: Data Collectionmentioning

confidence: 99%

Pain Intensity and Opioid Utilization in Response to CPAP Therapy in Veterans with Obstructive Sleep Apnea on Chronic Opioid Treatment

Jaoude

Lal

Vermont

et al. 2016

Journal of Clinical Sleep Medicine

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Study Objectives: Sleep fragmentation has been linked to poor pain tolerance and lowered pain threshold. Little evidence exists on whether continuous positive airway pressure (CPAP) adherence in veterans with obstructive sleep apnea (OSA) who are taking opioids for non-malignant pain would ameliorate pain and reduce consumption of opioids. Methods: A retrospective case-control study was performed at a VA sleep center. Pain intensity was assessed using the Numerical Categorical Scale prior to CPAP treatment and 12-mo follow-up. Opioids intake was assessed using the morphine equivalent daily dose (MEDD). Adherence to CPAP was evaluated with the built-in meter. Results: We reviewed 113 patients with OSA (apnea-hypopnea index [AHI] 35.9 ± 29.5) using a MEDD of 61.6 mg (range 5-980 mg) and a control group of 113 veterans with OSA (AHI 33.4 ± 27.3) on no opioids treatment. CPAP adherence was significantly lower at 12 mo in opioid-treated patients compared to controls (37% versus 55%; p = 0.01). Greater pain intensity was the only independent variable associated with CPAP non-adherence at 12-mo follow-up (p = 0.03). Compared to baseline, no significant difference was observed in pain intensity or consumption of opioids in CPAP adherent patients. I NTRO DUCTI O NChronic pain is a serious and highly prevalent condition among service members. Although the prevalence of chronic pain and opioid use associated with deployment is not well known, a recent report indicated that nearly half of a group of infantry soldiers who had seen combat in Afghanistan have reported experiencing chronic pain.1 The better body armor combined with advanced medical care on the battlefield had led to improved survival rates following serious residual injuries (such as limb amputations and severe nerve and musculoskeletal damage) caused by blasts or projectiles. The multiplicity of these wounds in soldiers, coupled with cognitive impairments associated with traumatic brain injury and mental health morbidity has caused an increase in dependency on opioids to suppress these ailments.The use of opioids has been associated with development of sleep-disordered breathing, including central apneas, ataxic breathing, and nocturnal hypoxemia.2-4 However, obstructive sleep apnea (OSA) is considered the predominant form of sleep-disordered breathing among veterans receiving chronic opioid therapy.5 However, this reduced pain sensitivity has been reported in healthy volunteers with induced rather than preexisting pain. It is speculated that the sleep disruption resulting from repeated arousals alters the nociceptive system, rendering it more susceptible to maladaptive plasticity. Preliminary investigations in healthy volunteers have suggested that although pain sensitivity is increased following sleep restriction, restoring sleep architecture ameliorates pain thresholds. 6,7 Further, treatment of underlying sleep apnea with continuous positive airway pressure (CPAP) has been associated with reduced hyperalgesia in patients with sleep-disordered breathing. ...

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Section: Data Collectionmentioning

confidence: 99%

Pain Intensity and Opioid Utilization in Response to CPAP Therapy in Veterans with Obstructive Sleep Apnea on Chronic Opioid Treatment

Jaoude

Lal

Vermont

et al. 2016

Journal of Clinical Sleep Medicine

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“…The in vitro formation of M3G and M6G was investigated in human liver microsomes (n = 5; HLS nos 18,21,34,36,46). Optimal incubation conditions were determined prior to the commencement of the kinetic and inhibition studies (see below).…”

Section: Microsomal Incubationsmentioning

confidence: 99%

“…Only one investigation using human liver microsomes has shown the possible involvement of more than one UGT isoform in M3G formation, with the suggested involvement of a high-affinity, low-capacity enzyme (with a mean K m and V max of 5.3 µ M and 18 nmol mg − 1 protein h − 1 ) and lowaffinity, high-capacity enzyme (with mean K m and V max of 1203 µ M and 653 nmol mg − 1 protein h − 1 ) [19]. Methadone, a µ -opioid receptor agonist, is the most widely used substitution treatment for opioid dependence [20] and is becoming increasingly accepted as a treatment for cancer pain [21]. Methadone exists as two stereo-isomeric forms, the levorotatory R-(-)-methadone and the dextrorotatory S-( + )-methadone.…”

Section: Introductionmentioning

confidence: 99%

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Morrish

Foster

Somogyi

2005

Brit J Clinical Pharma

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Differential in vitro inhibition of M3G and M6G formation from morphine by (R)-and (S)-methadone and structurally related opioids Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia AimsTo determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. MethodsM3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µ M ) and the mechanism of inhibition determined for (R)-and (S)-methadone (70-500 µ M ) using three microsomal samples. ResultsGlucuronide formation displayed single enzyme kinetics. The M3G V max (mean ± SD) was 4.8-fold greater than M6G V max (555 ± 110 vs. 115 ± 19 nmol mg − 1 protein h − 1 ; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg − 1 protein h − 1 ). K m values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 m M ; P = 0.89, 0.02; − 0.29, 0.32 m M ). M3G and M6G formation was inhibited ( P < 0.01) with a significant increase in the M3G/M6G ratio ( P < 0.01) for all compounds tested. Detailed analysis with (R)-and (S)-methadone revealed noncompetitive inhibition with (R)-methadone K i of 320 ± 42 µ M and 192 ± 12 µ M for M3G and M6G, respectively, and (S)-methadone K i of 226 ± 30 µ M and 152 ± 20 µ M for M3G and M6G, respectively. K i values for M3G inhibition were significantly greater than for M6G for (R)-methadone ( P = 0.017, 128; 55, 202 µ M ) and (S)-methadone ( P = 0.026, 75; 22, 128 µ M ). ConclusionsBoth methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadonemaintained patients and reduced relative formation of the opioid active M6G compared with M3G. IntroductionMorphine is the gold standard opioid for the treatment of moderate to severe acute and chronic pain. Morphine is primarily cleared via glucuronidation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal- [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17]. However, only UGT2B7 has been shown to form M6G [17,18]. The relative contribution of these isoforms to the overall glucuronidation of morphine is still unknown. Only one investigation using human liver microsomes has shown the possible involvement of more than one UGT isoform in M3G formation, with the suggested involvement of a high-affinity, low-capacity enzyme (with a mean K m and V max of 5.3 µ M and 18 nmol mg − 1 protein h...

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“…Previous experiences have shown that a failure to respond to one opioid does not mean failure to respond to all opioids, and opioid switching may allow better pain control and decrease the intensity of adverse disabling effects. [1][2][3][4][5] The keystone to the rationale behind opioid substitution is incomplete cross tolerance, although the exact reason why opioid substitution is successful remains unclear. In some patients, poorly responsive pain may arise because of the development of analgesic tolerance to an opioid, whereas tolerance to adverse effects does not develop to the same extent.…”

Section: Introductionmentioning

confidence: 99%

Rapid Switching Between Transdermal Fentanyl and Methadone in Cancer Patients

Mercadante

Ferrera

Villari

et al. 2005

JCO

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A B S T R A C T PurposeThe aim of this study was to examine the clinical effects of switching from transdermal (TTS) fentanyl to methadone, or vice versa, in patients with a poor response to the previous opioid. Patients and MethodsA prospective study was carried out on 31 patients who switched from TTS fentanyl to oral methadone, or vice versa, because of poor opioid response. A fixed conversion ratio of fentanyl to methadone of 1:20 was started and assisted by rescue doses of opioids, and then doses were changed according to clinical response. Pain and symptom intensity, expressed as distress score, were recorded before switching doses of the two opioids and after subsequent doses. The number of changes of the daily doses, time to achieve stabilization, and hospital stay were also recorded. ResultsEighteen patients were switched from TTS fentanyl to methadone, and seven patients were switched from methadone to TTS fentanyl. A significant decrease in pain and symptom intensity, expressed as symptom distress score, was found within 24 hours after switching took place in both directions. Unsuccessful switching occurred in six patients, who were subsequently treated with an alternative therapy. ConclusionA rapid switching using an initial fixed ratio of fentanyl to methadone of 1:20 is an effective method to improve the balance between analgesia and adverse effects in cancer patients with poor response to the previous opioid. No relationship between the final opioid dose and the dose of the previous opioid has been found.

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Switching From Morphine to Methadone to Improve Analgesia and Tolerability in Cancer Patients: A Prospective Study

Cited by 235 publications

References 50 publications

Pain Intensity and Opioid Utilization in Response to CPAP Therapy in Veterans with Obstructive Sleep Apnea on Chronic Opioid Treatment

Pain Intensity and Opioid Utilization in Response to CPAP Therapy in Veterans with Obstructive Sleep Apnea on Chronic Opioid Treatment

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Rapid Switching Between Transdermal Fentanyl and Methadone in Cancer Patients

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