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Bioavailability of Methadone After Sleeve Gastrectomy: A Planned Case Observation

  • Magnus Strømmen
    Correspondence
    Address correspondence to: Magnus Strømmen, RN, MSc, Centre for Obesity Research, Clinic of Surgery, St. Olav University Hospital, PO Box 3250 Sluppen, Trondheim 7006, Norway.
    Affiliations
    Centre for Obesity Research, Clinic of Surgery, St. Olav University Hospital, Trondheim, Norway

    Department of Neuroscience, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
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  • Arne Helland
    Affiliations
    Department of Clinical Pharmacology, Clinic of Laboratory Medicine, St. Olav University Hospital, Trondheim, Norway

    Department of Laboratory Medicine, Children’s and Women’s Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
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  • Bård Kulseng
    Affiliations
    Centre for Obesity Research, Clinic of Surgery, St. Olav University Hospital, Trondheim, Norway
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  • Olav Spigset
    Affiliations
    Department of Clinical Pharmacology, Clinic of Laboratory Medicine, St. Olav University Hospital, Trondheim, Norway

    Department of Laboratory Medicine, Children’s and Women’s Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
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Open AccessPublished:May 12, 2016DOI:https://doi.org/10.1016/j.clinthera.2016.04.033

      Abstract

      Objective

      Morbidly obese patients on opioid-replacement therapy may be at risk for treatment refusal with regard to bariatric surgery. However, patients on opioid replacement may have the personal skills to facilitate the lifestyle changes required for successful outcomes after bariatric surgery. This planned case observation assessed the effects of sleeve gastrectomy on the pharmacokinetic properties of methadone.

      Methods

      A white woman in her 40s on methadone maintenance therapy and with morbid obesity was referred for bariatric surgery. Serial blood samples for methadone concentration measurements were obtained before and at 5 days and 1, 7, and 11 months after surgery.

      Findings

      Serum methadone concentrations increased from before to 5 days after surgery and continued to increase for 7 months thereafter. The predose measurement at 11 months postoperatively suggests a further increase compared with the previous predose measurements.

      Implications

      Clinicians should beware the potential for altered effects of methadone after bariatric surgery. We recommend that serum concentrations be routinely measured pre- and postoperatively, and that the dose be adjusted according to these measurements and regular clinical assessments.

      Key words

      Introduction

      Although there are no absolute contraindications to bariatric surgery,
      SAGES Guidelines Committee
      SAGES guideline for clinical application of laparoscopic bariatric surgery.
      most bariatric surgeons consider that patients with ongoing illicit drug use should not undergo such procedures.
      • Bauchowitz A.U.
      • Gonder-Frederick L.A.
      • Olbrisch M.E.
      • et al.
      Psychosocial evaluation of bariatric surgery candidates: a survey of present practices.
      The lack of clear recommendations within this field makes morbidly obese patients on opioid-replacement therapy a subgroup at risk for treatment refusal.
      There is little evidence to provide guidance on these matters. Of the few relevant studies that exist, one found patients with past substance abuse to be at higher risk for dropout during the assessment process before bariatric surgery.
      • Sockalingam S.
      • Cassin S.
      • Crawford S.A.
      • et al.
      Psychiatric predictors of surgery non-completion following suitability assessment for bariatric surgery.
      However, a study evaluating weight loss 2 years after gastric bypass found that patients who previously and successfully had participated in treatment for substance abuse (alcohol or drugs) achieved more weight loss compared with patients with no history of substance abuse.
      • Clark M.M.
      • Balsiger B.M.
      • Sletten C.D.
      • et al.
      Psychosocial factors and 2-year outcome following bariatric surgery for weight loss.
      The authors hypothesized that patients with such a history can gain valuable insight into personal skills relevant for lifestyle change, as well as draw strength from their experience with abstinence support programs.
      Both preclinical and clinical studies have reported that chronic exposure to opioid μ-receptor agonists leads to sweet taste preference.
      • Mysels D.J.
      • Sullivan M.A.
      The relationship between opioid and sugar intake: Review of evidence and clinical applications.
      It is also known that patients entering methadone maintenance therapy gain weight: One study found that women 2 years into treatment had increased on average 17.5% in weight.
      • Fenn J.M.
      • Laurent J.S.
      • Sigmon S.C.
      Increases in body mass index following initiation of methadone treatment.
      Consequently, occasional referrals of patients on methadone maintenance are likely to occur in bariatric clinics.
      Clinicians may be reluctant to provide bariatric surgery in patients on opioid-replacement therapy, for fear of adverse outcomes. Uncertainties concerning the effects of the procedure on pharmacokinetics may contribute to such hesitation. Several mechanisms of bariatric surgery may influence the bioavailability of pharmaceuticals, such as shifts in gastric pH, changes in gastrointestinal transit time, reduced absorptive surface area, and altered presystemic drug metabolism. The effects of bariatric surgery on pharmacokinetic properties are known for only a few medications.
      • Edwards A.
      • Ensom M.H.
      Pharmacokinetic effects of bariatric surgery.
      Neither methadone nor buprenorphine, the drugs most commonly used for opioid-replacement therapy, are among these.
      This planned case observation is the first systematic evaluation of the possible effects of sleeve gastrectomy on methadone pharmacokinetics.

      Case Description

      A white woman in her 40s on methadone maintenance therapy and with morbid obesity was referred for bariatric surgery at a Norwegian university hospital. She had a 27-year history of illicit drug abuse and had injected heroin for 10 years before she entered a rehabilitation program that included opioid-replacement therapy with methadone ~10 years before presentation. After starting methadone therapy, she had gained ~30 kg in weight. At referral to hospital, her height was 159 cm, her weight was 127.8 kg, and her body mass index (BMI) was 50.6 kg/m2. She presented with multiple complications of morbid obesity, including type 2 diabetes mellitus, obstructive sleep apnea, and depression. She also had hyperparathyroidism and was hepatitis B and C positive. In addition to methadone 120 mg/d (a dose that had been stable for several years), her drug therapy consisted of metformin 1600 mg/d and sitagliptin 100 mg/d for diabetes, fesoterodine 16 mg/d for urinary incontinence, pregabalin 900 mg/d for neuralgia, and lactulose as needed for constipation.
      The patient underwent a multidisciplinary review, including a psychiatric assessment, in the bariatric clinic. She was informed about the lack of scientific evidence concerning the effects on the pharmacokinetic properties of methadone, and provided written consent to undergo surgery, including being followed up for 15 years for the evaluation of long-term effects. The authors also received approval for performing the study from the regional ethics committee. After completing a mandatory patient-education program, the patient was scheduled for laparoscopic sleeve gastrectomy and followed a liquid very-low-calorie diet the 3 weeks before surgery.
      The patient’s preoperative weight and BMI were 117.0 kg and 46.3 kg/m2. Surgery took place with the patient under general anesthesia, and the patient had an epidural catheter placed for postoperative pain relief. The need for epidural analgesia prolonged her hospitalization, extending the regular stay of 1 to 2 days to 8 days. She received her regular dose of 120 mg methadone both on the day of surgery and on the subsequent in-hospital days.
      One year after surgery, her weight and BMI had decreased to 92.1 kg and 36.4 kg/m2, respectively, representing a 46.3% loss of her excess weight (using the upper BMI limit for normal weight, i.e. 25 kg/m2, as reference). Her physical functioning had improved and she had stopped taking antidiabetic medication. The methadone dose was kept unchanged at 120 mg/d throughout the first postoperative year.
      Serial blood samples for methadone concentration measurements were obtained at 8 days preoperatively, as well as at 5 days, 1 month, and 7 months postoperatively. Sampling took place at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, and 24 hours after methadone ingestion. Moreover, a single sample was obtained 24 hours after methadone ingestion at 11 months postoperatively. Serum concentrations of total methadone as well as of its enantiomers R-methadone and S-methadone were measured with an LC/MS method developed at our laboratory.
      • Stallvik M.
      • Nordstrand B.
      • Kristensen O.
      • et al.
      Corrected QT interval during treatment with methadone and buprenorphine – relation to doses and serum concentrations.
      Key pharmacokinetic variables of methadone were calculated by means of the pharmacokinetic analysis software package Kinetica version 5.0 (Thermo Scientific, Waltham, Massachusetts). The patient was genotyped for the cytochrome P-450 (CYP) enzymes CYP2B6, CYP3A4, and CYP3A5, which are involved in the metabolism of methadone,
      • Kapur B.M.
      • Hutson J.R.
      • Chibber T.
      • et al.
      Methadone: a review of drug-drug and pathophysiological interactions.
      by allele-specific polymerase chain reaction (PCR).
      • Crettol S.
      • Deglon J.J.
      • Besson J.
      • et al.
      Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment.
      • Lunde I.
      • Bremer S.
      • Midtvedt K.
      • et al.
      The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients.

      Results

      The time–concentration curve of methadone in this patient is presented in the Figure. In general, the serum concentrations of methadone were increased from the sampling preoperatively to 5 days postoperatively, and continued to increase during the first 7 months after surgery. The single predose measurement 11 months postoperatively suggested a further increase compared with the previous predose measurements. Key pharmacokinetic data are presented in the Table.
      Figure
      FigureSerum concentrations of methadone in a woman undergoing bariatric surgery by sleeve gastrectomy.
      TablePharmacokinetic variables based on the concentrations of total (R + S) methadone and of the active enantiomer R-methadone in a woman undergoing bariatric surgery with sleeve gastrectomy.
      ParameterPreoperatively (Baseline)Postoperative Day 5Postoperative Month 1Postoperative Month 7
      Total (R + S) methadone
       C0, nmol/L50864511661481
       Cmax, nmol/L945141421282564
       Cmax/C0 ratio1.862.191.821.73
       Tmax, h2.51.51.51.0
       AUC0–24, nmol/L × h14,36820,19834,92044,983
       AUC0–24, % increase
      Compared to AUC0–24 preoperatively.
      041143213
       t½, h29.336.537.137.2
      R-methadone
       C0, nmol/L402423766940
       Cmax, nmol/L61674812061379
       Cmax/C0 ratio1.531.771.571.47
       Tmax, h2.51.51.51.0
       AUC0–24, nmol/L × h10,45311,94622,40127,460
       AUC0–24, % increase
      Compared to AUC0–24 preoperatively.
      014114163
       t½, h43.948.459.454.8
      low asterisk Compared to AUC0–24 preoperatively.
      The AUC of the active enantiomer R-methadone increased less than did that of total methadone, with 14%, 114%, and 163% increases at 5 days, 1 month, and 7 months after surgery, respectively. In accordance with this finding, the proportion of R-methadone of the total methadone concentration decreased sharply shortly after surgery, and then remained stable. The proportions of R-methadone of the total methadone concentration were 76% at t0 and 62% at Tmax preoperatively, and 65% at t0 and 52% at Tmax postoperatively. Genotyping revealed the following genotypes: CYP2B6, *1/*1; CYP3A4, *1/*1; and CYP3A5, *1/*3.
      As methadone is known to prolong the QT interval on ECG in a dose-related manner, increasing the risk for torsades de pointes ventricular tachycardia,
      • Stallvik M.
      • Nordstrand B.
      • Kristensen O.
      • et al.
      Corrected QT interval during treatment with methadone and buprenorphine – relation to doses and serum concentrations.
      we obtained pre- and postoperative ECGs. Immediately preoperatively, the QT interval corrected for heart rate (QTc) was 425 ms, whereas it was 435 ms at 10 months postoperatively.

      Discussion

      In this planned case observation, we observed marked changes in the pharmacokinetic properties of methadone after the patient had undergone sleeve gastrectomy, with a large increase in drug exposure and a shorter Tmax compared with baseline. The total drug exposure, as expressed by the AUC, increased progressively throughout the postoperative period, and 7 months postoperatively it was 3-fold the baseline value. This large increase can be explained only by a substantially greater bioavailability. The Tmax decreased from 2.5 hours before surgery to 1 hour at 7 months after surgery. The t1/2 increased slightly immediately postoperatively, then it remained stable. The active enantiomer, R-methadone, showed similar changes, but to a somewhat lesser extent.
      In most patients, methadone bioavailability is >80%; thus, the overall potential for increased bioavailability of methadone would be expected to be low and generally not exceed a 20% increase. However, a large interindividual variability in bioavailability, with values ranging from 36% to 100%, has been described.
      • Kapur B.M.
      • Hutson J.R.
      • Chibber T.
      • et al.
      Methadone: a review of drug-drug and pathophysiological interactions.
      Genotyping showed that the patient had the CYP3A5 *1/*3 genotype, signifying an increased metabolic capacity for CYP3A substrates such as methadone compared with the general white population.
      • De Fazio S.
      • Gallelli L.
      • De Siena A.
      • et al.
      Role of CYP3A5 in abnormal clearance of methadone.
      In patients expressing active CYP3A5, the presence of this enzyme increases the presystemic metabolism of CYP3A substrates, leading to lesser bioavailability.
      • De Fazio S.
      • Gallelli L.
      • De Siena A.
      • et al.
      Role of CYP3A5 in abnormal clearance of methadone.
      This finding is in accordance with the low preoperative serum concentration of methadone in the present patient (a concentration below the 10th percentile among patients taking a dose of 120 mg/d, according to unpublished data from our laboratory’s therapeutic drug monitoring database, 2015). The potential for large increases in the bioavailability of drugs metabolized by CYP3A after bariatric surgery, particularly in patients who express active CYP3A5, has been reported previously for atorvastatin.
      • Skottheim I.B.
      • Jakobsen G.S.
      • Stormark K.
      • et al.
      Significant increase in systemic exposure of atorvastatin after biliopancreatic diversion with duodenal switch.
      Sleeve gastrectomy decreases gastric volume without inducing malabsorption. No portion of the small intestine is bypassed, and the pyloric function remains intact.
      • Stefater M.A.
      • Wilson-Pérez H.E.
      • Chambers A.P.
      • et al.
      All bariatric surgeries are not created equal: insights from mechanistic comparisons.
      Thus, it may seem surprising that such a procedure could dramatically influence drug bioavailability. Logically, because no part of the intestine is removed or bypassed, the amount of CYP3A in the intestinal wall and thus the extent of presystemic metabolism would be expected to be unaffected. However, sleeve gastrectomy is associated with a more rapid emptying of gastric contents into the intestine after ingestion,
      • Melissas J.
      • Leventi A.
      • Klinaki I.
      • et al.
      Alterations of global gastrointestinal motility after sleeve gastrectomy: a prospective study.
      a phenomenon often referred to as "dumping." The decrease in Tmax confirms the occurrence of this mechanism in our patient. Rapid gastric emptying after sleeve gastrectomy may lead to a substantially greater drug concentration in the duodenum after methadone intake. We hypothesize that the increased drug concentration may overwhelm CYP3A enzyme capacity in the intestinal wall and possibly also during the first pass through the liver, causing a higher proportion of the drug to reach the systemic circulation.
      Other possible explanations for the observed pharmacokinetic changes should be taken into consideration. Systemic inflammation may downregulate the expression of both CYP enzymes and drug transporters such as p-glycoprotein and increase the plasma concentration of the acute phase protein α1-acid glycoprotein, to which methadone is highly bound.
      • Kapur B.M.
      • Hutson J.R.
      • Chibber T.
      • et al.
      Methadone: a review of drug-drug and pathophysiological interactions.
      Such changes may possibly have contributed to the increased serum concentration of methadone immediately postoperatively. However, this concept cannot explain the further increases in methadone concentration during the subsequent months. Moreover, we cannot rule out the possibility that inadequate medication adherence contributed to the observed changes. However, because the methadone concentrations at t0 and t24 were almost identical in all 4 sample series, nonadherence does not seem likely. The patient’s considerable weight loss has reduced the total volume of distribution of the methadone. However, as the concentration at steady state is primarily related to clearance and not to the volume of distribution, the key question is whether a weight loss like this could reduce clearance, such as via a decrease in liver mass. The patient’s lean body mass was reduced by 9.3% from 1 to 7 months postoperatively. Even if the total liver mass would be expected to have decreased by the same order of magnitude, we consider that the contribution of such an effect would explain only a small part of the observed increases in the methadone concentration. Finally, to our knowledge, the patient did not at any point use medications known to influence CYP3A metabolism, which could otherwise have influenced the pharmacokinetic properties of methadone.
      Pre- and postoperative ECGs did not reveal a significant increase in the QT interval; however, the risk for QT prolongation in such patients should definitively be borne in mind as it is a known dose-dependent adverse effect of methadone.
      • Stallvik M.
      • Nordstrand B.
      • Kristensen O.
      • et al.
      Corrected QT interval during treatment with methadone and buprenorphine – relation to doses and serum concentrations.
      A higher and more rapidly occurring peak concentration might increase the rewarding and intoxicating effects of methadone, which could be detrimental in previous addicts, and might even cause respiratory depression. Unfortunately, we do not have systematic clinical observations of the patient during the postoperative period.

      Conclusion

      We conclude that sleeve gastrectomy has the potential to significantly increase the bioavailability of and decrease the Tmax of methadone, probably due to accelerated gastric emptying. This finding especially applies to individuals with a low preoperative bioavailability, such as that caused by genetically determined or pharmacologically induced increased CYP3A metabolism. Clinicians should beware the potential for altered drug effects of methadone after bariatric surgery. We recommend that serum concentrations be routinely measured pre- and postoperatively, and that the dose be adjusted according to these measurements and regular clinical assessments.

      Conflicts Of Interest

      The authors have indicated that they have no conflicts of interest with regard to the content of this article.

      Acknowledgment

      We thank the staff at the Clinical Research Facility at St. Olav University Hospital, Trondheim, Norway, for clinical and technical support. There were no external sources of funding.

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