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Withdrawal symptoms during chronic transdermal fentanyl administration managed with oral methadone

      To the Editor:
      Fentanyl is a strong opioid widely used as a transdermal patch in patients with moderate to severe cancer-related pain. According to the manufacturer, fentanyl can be delivered in a patch to provide continuous, controlled systemic delivery (dictated by the system rather than the skin) of fentanyl for “up to 72 hours.”
      An opioid withdrawal syndrome (WS) has been reported in up to 10% of patients in the first 24–48 hours after switching from morphine to transdermal fentanyl (TF).
      • Davies A.N.
      • Bond C.
      Transdermal fentanyl and the opioid withdrawal syndrome.
      • Hunt R.
      Transdermal fentanyl and the opioid withdrawal syndrome.
      • Higgs C.M.B.
      • Vella-Bricant J.
      Withdrawal with transdermal fentanyl.
      • Gourlay G.K.
      Treatment of cancer pain with transdermal fentanyl.
      The frequent symptoms of this syndrome include flu-like symptoms, tachycardia, abdominal cramps and diarrhea, nausea, profuse sweating, and agitation. These symptoms could occur even if the cancer-related pain was under control in most cases. They could be relieved by small doses of morphine.
      • Hunt R.
      Transdermal fentanyl and the opioid withdrawal syndrome.
      Han et al.
      • Han P.K.J.
      • Arnold R.
      • Bond G.
      • et al.
      Myoclonus secondary to withdrawal from transdermal fentanyl: a case report and literature review.
      reported a case of myoclonus that occurred when fentanyl was discontinued and also occurred every third day following patch application. The symptom was controlled by increasing the TF dose frequency to 48 hours.
      What has never been reported in the literature is the onset of a typical withdrawal syndrome during chronic, continuous TF administration in fentanyl-tolerant cancer patients. We describe the clinical manifestations of this syndrome and describe how the symptoms were successfully managed by switching all the patients to oral methadone. Table 1 shows patients' characteristics, fentanyl therapy, pain intensity, withdrawal symptoms, and methadone dosages needed to manage the WS and pain.
      Table 1Patient Characteristics, Fentanyl Therapy, and Related Symptoms, Pain Intensity, Withdrawal Symptoms, Methadone Dosages to Reverse Withdrawal Syndrome, and to Manage the Pain
      Patient, Sex, Age, PathologyFentanyl Administration Duration Before the Onset of Withdrawal SymptomsDrug Therapy, Dosages, and Problems Referred by the Patients During the First Visit to the Pain Therapy and Palliative Care Unit of the Milan NCIPain Intensity
      Pain intensity assessed by a 6-level verbal scale (none, very mild, mild, moderate, severe, very severe).
      on Fentanyl Patch
      Onset and Type of Withdrawal SymptomsSwitching to Oral MethadoneAdverse Effects and/or Withdrawal Symptoms after Switching to Oral MethadonePain Intensity
      Pain intensity assessed by a 6-level verbal scale (none, very mild, mild, moderate, severe, very severe).
      on Oral Methadone
      CA Male 60 Kidney cancer Bone and lung metastases5 monthsFentanyl patch: 75 μg/h every day↑to 100 μg/h and then to 150 μg/h every day with no analgesic benefit. Then↓to 75 μg/h every day  + SRM 10 p.r.n. Dexamethasone 4 mg/day orally“Severe/very severe”After 18 hours from the application of new patch: tremors, profuse sweating, palpitations and anguish, insomnia, general malaiseMethadone 10 mg t.i.d. for 3 days, then, over a month, progressive↑of methadone till 20 mg t.i.d. + 20 mg of SC morphine twice a day as rescue medicationNo adverse effects, no withdrawal symptoms“None/very mild” at rest. “Moderate” on movement and consid- ered as satis- factory pain control by the patient
      TM Female 58 Adenoid-cystic carcinoma of the palate4 monthsFentanyl 25 μg/h every 72 hours. In the previous week she had↑the patch to 50 μg/h. However, as she had complained of severe drowsiness, she went back to 25 μg/h till the first visit“None” for the first 2 days with 25 μg/h patch.After 48 hours from the application of a new patch: pain, profuse sweating, tremors, agitation, anxiety, general malaiseMethadone 5 mg t.i.d. After 5 days↓4 mg t.i.d. Within the 1st month↓till to 1 mg t.i.d.No adverse effects, no withdrawal symptoms“None”
      MA Female 42 Submandibular adenoid-cystic carcinoma18 daysFentanyl 25 μg/h every 60 hours after switching from 50 mg/day of SRM due to nausea, vomiting and constipation“Mild/very mild”After 24–26 hours from the application of the new patch: asthenia, distress, anxiety, profuse sweating, and general malaise. Symptoms disappeared with 30 mg of SRMMethadone 5 mg t.i.d. + 30 mg of SRM p.r.n., then↓methadone to 2 mg t.i.d. and no rescue dose of SRM was requiredNo adverse effects, no withdrawal symptoms“None”
      ↓ = decrease; ↑ = increase; SRM = short-release morphine (oral drops); SC = subcutaneous.
      a Pain intensity assessed by a 6-level verbal scale (none, very mild, mild, moderate, severe, very severe).
      The three patients had been wearing TF for various lengths of time without changing the drug. No patient had a history of chemical dependency or alcohol abuse, or renal or liver failure. None had fever or had been exposed to heat that could have increased the release of the drug from the patch. The patients had not taken inducers of CYP3A4 that may enhance metabolism and consequently increase the clearance of fentanyl.
      The first patient (CA) arrived at our unit with severe pain, and was very exhausted and frustrated because of tremors, insomnia, sweating, palpitations, and generalized malaise. The patient told us that he had been prescribed different dosages of TF and had tried changing the patch every 60 hours, then 48 hours, and finally every 24 hours without any benefit to pain or WS. Supplemental doses of other opioids (morphine, tramadol) had been administered while he was wearing the patch, without pain control and only slightly reduced WS intensity.
      The patient TM had very good pain control (scored as “None”) for two days with TF dose of 25 μg/h. However, every third day following patch application, she complained of WS. The increase of the dosage to 50 μg/h produced severe drowsiness.
      The patient MA developed WS after 24–26 hours of the new patch application. The first WS occurred 18 days after she switched from oral morphine to TF.
      With the patients' consent, we considered switching to oral methadone to reverse withdrawal symptoms. However, as no published conversion tables exist regarding fentanyl with methadone, we had to calculate empirically a safe and effective methadone dose with respect to morphine and then from morphine to methadone. We used a conversion table applied routinely in our unit,
      • Burza M.
      • Ginobbi P.
      • Fusco G.
      • et al.
      La via transdermica come alternativa agli oppioidi per os nel dolore oncologico.
      on which 25 μg/h of TF = 60 mg/day oral morphine; 50 μg/h = 90 mg/day; 75 μg/h = 120 mg/day; and 100 μg/h = 180 mg/day of oral morphine. We titrated the dose up or down until a balanced analgesia was reached versus the adverse effects. The methadone dose was calculated using ratios of 1:4 (1 mg of methadone = 4 mg of morphine), 1:8, and 1:12 with respect to different equivalent daily doses of oral morphine according to our previous published data.
      • Ripamonti C.
      • Groff L.
      • Brunelli C.
      • et al.
      Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio?.
      In patients with uncontrolled severe pain and withdrawal symptoms, a 33% increase in the methadone doses was considered.
      • Mercadante S.
      • Casuccio A.
      • Fulfaro F.
      • et al.
      Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.

      1. Comment

      It is common in clinical practice to change the fentanyl patch before the recommended 72 hours to reach pain control. It is unusual, however, to observe the onset of WS during TF therapy even when dosages are increased and administration intervals are reduced. To explain the possible causes of the WS in our patients, we would consider the following points:
      • 1.
        Published data show that TF application intervals have to be shortened to 48–60 hours in about 25% of patients
        • Gourlay G.K.
        Treatment of cancer pain with transdermal fentanyl.
        • Portenoy R.K.
        • Southam M.A.
        • Gupta S.K.
        • et al.
        Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics.
        and to 48 hours in 11–43% of patients;
        • Grond S.
        • Radbruch L.
        • Lehmann K.A.
        Clinical pharmacokinetics of transdermal opioids. Focus on transdermal fentanyl.
        this is in agreement with the TF pharmacokinetics. In our patients, the patch was renewed every 24–48 hours.
      • 2.
        The application systems are designed to deliver fentanyl at a constant rate over a period of 72 hours. The rate-controlling membrane of the drug reservoir delivery system controls the rate of delivery of drug to the skin and influences about 50% of the rate of transdermal absorption.
        • Gourlay G.K.
        Treatment of cancer pain with transdermal fentanyl.
        In 2 studies,
        • Gourlay G.K.
        Treatment of cancer pain with transdermal fentanyl.
        • Portenoy R.K.
        • Southam M.A.
        • Gupta S.K.
        • et al.
        Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics.
        investigators noted considerable inter- and intrapatient variation with respect to the expected and actual rate of fentanyl delivered from the reservoir over the range 25 to 125 μg/h. Moreover, the observed variation in individual bioavailabilities may indicate that absorption varies between patients.
      • 3.
        A large intersubject variability has been found regarding fentanyl concentration and other pharmacokinetic parameters. Individual differences account for most of the variability. The pharmacokinetic variability may be explained partly due to different skin permeability, regional blood flow, protein binding, and partly due to different clearance. After several sequential 3-day (72 h) application intervals, steady-state plasma fentanyl concentrations are achieved, which can be maintained for as long as the TF is renewed.
      In a study that investigated 10 cancer patients wearing 5 consecutive patches (100 μg/h), during treatment with the fifth patch, repeated measurements were performed. The highest blood fentanyl concentrations at steady-state were measured on the first day.
      • Portenoy R.K.
      • Southam M.A.
      • Gupta S.K.
      • et al.
      Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics.
      Steady-state serum concentrations were approached by the second dose of TF and the kinetics were stable with repeated dosing; no significant differences in serum fentanyl concentrations were observed before the second through fifth doses.
      • Portenoy R.K.
      • Southam M.A.
      • Gupta S.K.
      • et al.
      Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics.
      As steady-state is approached, there appears to be no significant alteration in drug absorption or metabolism.
      • Portenoy R.K.
      • Southam M.A.
      • Gupta S.K.
      • et al.
      Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics.
      Our patients presented a WS at the time (on the first day in two patients) when blood fentanyl concentration should have been highest at steady-state. In our patients, the withdrawal symptoms may have been related to rapid decay of serum fentanyl concentration after renewal of the patch. It is important to acknowledge, however, that we do not have direct evidence of this (e.g., serum measurements of fentanyl) and/or a rapid and inconstant skin absorption rate.
      Our three patients had the WS successfully managed by switching to oral methadone. This led to a consistent reduction in pain intensity with no adverse effects. The dose ratio we used for switching from TF to oral methadone was shown to be safe and effective.
      In conclusion, patients who are receiving chronic TF administration, who have not been recently switched from another opioid, and who have been receiving a stable dose may present with WS. This indicates that the patients treated with TF must undergo frequent assessment, not only during the titration phase but also during prolonged treatment. In patients wearing TF, the causes of WS should be investigated further.

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