TREATMENT of chronic pain in patients with a history of opioid addiction is difficult since tolerance to the opioid agonist effects may require extremely large opioid doses for pain control. Furthermore, insufficient pain control may be hard to discern from craving for more opioids. Although drug-free periods, also called “drug holiday,” can reestablish sensitivity to drugs used to treat Parkinson disease and schizophrenia 1,2this strategy has not been described for patients with chronic pain presenting with tolerance to opioids.
We report an opioid addicted patient with intractable cancer pain during methadone substitution therapy in whom antagonist supported opioid detoxification and a drug holiday reestablished sensitivity to opioids and improved cancer pain.
A 35-yr-old man with a history of hemipelvectomy 2 yr ago for treatment of chondrosarcoma was admitted because of unbearable pain in the right leg (dermatomes L3–S2) described as burning and stabbing with a pain score of 9 - 10 on an 11 point (0–10) numeric rating scale (NRS). Examination also revealed paralysis of the right leg caused by extended tumor infiltration of the right lumbosacral plexus. The patient had a history of heroin addiction and had been treated with L-methadone (120 mg/day) as a substitution therapy to avoid withdrawal symptoms. Therapy was started with sustained-release morphine (60 mg/day p.o.) but had to be increased during 24 h to 300 mg/day intravenous morphine hydrochloride without amelioration of pain.
To discriminate between craving for opioids and insufficient control of neuropathic pain a lumbar epidural catheter was inserted (interspace: L3/L4) and bupivacaine (0.25%, 10 ml) injected every 4–6 h while methadone was continued. This resulted in complete pain relief and the patient didn't ask for additional opioids. Intravenous morphine could be stopped and, to prepare a long-term oral medication regimen, dipyrone (3 g/day p.o.), dexamethasone (14 mg/day p.o.), amitriptyline (125 mg/day p.o.), and carbamazepine (1200 mg/day p.o.) were started thereafter.
After 4 weeks of epidural treatment, however, pain increased despite increasing dosages of epidural bupivacaine. Therefore, a short and unsuccessful attempt with high dose (1368 mg/day) intravenous morphine therapy was made but changed to epidural morphine injection, while oral therapy with L-methadone, dipyrone, amitriptyline, dexamethasone, and carbamazepine was continued. As much as 30 mg/h of epidural morphine was required for moderate pain relief.
Since long-term administration of these large opioid dosages is not feasible as a long-term home therapy, we performed an antagonist-supported detoxification procedure during general anesthesia so as to resensitize the opioid receptor system.
The L-methadone administration was stopped 7 days before detoxification without evoking withdrawal symptoms. Following anesthesia with propofol, tracheal intubation, and mechanical ventilation, the opioid receptor blockade was performed by intravenous administration of the opioid receptor antagonist naloxone (12.4 mg naloxone intravenous within 1 h), as described previously. 3Opioid receptor blockade was maintained by naloxone (0.8 mg/h intravenous for 24 h), and followed by the orally active opioid receptor antagonist naltrexone (50 mg/day p.o.) for 1 week. Withdrawal symptoms were minimized by administration of the α2-adrenoceptor antagonist clonidine (10 μg/kg + 2–5 μg/kg × h intravenous) 4and the patient was extubated 8 h after induction of general anesthesia. After completion of the procedure, the patient had moderate withdrawal symptoms treated by titrating doses of clonidine and amitriptyline per os until the symptoms were controlled. No significant episodes of nausea, vomiting, or diarrhea occurred. Cancer pain following opioid receptor blockade was completely relieved by epidural bupivacaine (0.25%, 5 ml/h) via a newly inserted lumbar epidural catheter (interspace: L3/L4) allowing a drug holiday of 3 weeks (fig. 1).
Subsequently, the epidural catheter was removed and sufficient pain relief (NRS ≤ 3) was achieved by a moderate dose of sustained-release morphine (90 mg p.o.) combined with dipyrone (3 g/day p.o.), dexamethasone (12 mg/day p.o.), amitriptyline (125 mg/day p.o.), carbamazepine (1200 mg/day p.o.), and clonidine (900 μg/day p.o.).
Palliative fractionated radiotherapy was started after 2 weeks of drug holiday. When treatment had been switched completely to oral medications and the epidural catheter was extracted after 3 weeks of drug holiday the patient had received 9.0 Gy of a total dose of 59.4 Gy. Unfortunately, radiation did not decrease the tumor size nor prevent tumor progression.
The patient was fully active and remained pain free under oral medications on discharge and no complications due to detoxification and analgesic treatments were observed. Pain control with sustained release morphine (≤1.5 g/day) was effective for another 8 months despite extensive tumor progression leading to a large ulcer involving his leg and gluteal region. Eight months after the end of opioid holiday subcutaneous morphine (∼600 mg/day), therapy was started one week before the patient's death.
After long-term opioid administration, the vanishing analgesic effect of opioids in patients with intractable pain may be overcome by an opioid free period (drug holiday) following antagonist supported detoxification from opioids.
Neuropathic pain caused by tumor invasion of a plexus or peripheral nerve may be refractory to therapy. In our patient, tricyclic antidepressants considered to be most effective in neuropathic pain 5were ineffective. Although the effectiveness of opioid therapy is still controversial, 6opioid treatment has been recommended in patients with severe chronic neuropathic pain. 7However, in patients with a history of opioid abuse pain therapy may require much higher opioid dosages to achieve any analgesic effect. 8
Opioid tolerance is suspected when increasing opioid dosages are required to obtain a given effect. 9While its underlying pharmacokinetic and pharmacodynamic mechanisms are not yet fully understood chronic opioid administration decreases μ-opioid receptor density in several brain regions 10and uncouples opioid receptors from their second messenger system. 11Tolerance to analgesic effects of opioids develops in at least 15% of cancer patients receiving opioids parenterally 12and cross tolerance between systemic and epidural morphine can occur. Of interest, in patients receiving long term oral opioid therapy, three times higher doses of epidural opioids are required for postoperative pain therapy compared to opioid naive patients. 13We did not establish continuous intrathecal or epidural opioid infusion with an implanted pump system, 14since this was not considered feasible given a short life expectancy, a difficult social background, and little compliance. We also did not consider a L3-S2 neurolytic spinal block since the risk of side effects such as lower extremity paralysis or loss of bowel or bladder control was considered inappropriate.
When managing pain refractory to high-dose opioid therapy, changing the route of drug administration or switching to another opioid with a different structure may be useful. 15,16In our patient, we had already used two opioids (methadone and morphine) without success and also had temporarily changed from enteral to epidural application. Therefore, we could not switch therapy from 720 mg/day epidural morphine to oral administration, since this epidural dose is equivalent to approximately 21 g/day oral morphine, 17which is not successfully applicable in this dose.
To reestablish sensitivity to opioids, we performed an antagonist supported detoxification from opioids during general anesthesia followed by an opioid-free interval recommended as an alternative to conventional opioid withdrawal treatment in addicts. 18Gold et al. mentioned antagonist supported detoxification from opioids in two chronic pain patients 19with a reduction in the opioid dose observed after detoxification. Unfortunately, detailed information was not provided.
In our patient, anesthesia-supported detoxification from opioids combined with analgesia provided by epidural bupivacaine allowed control of his otherwise untreatable pain and reestablished sensitivity to orally administered opioids, allowing the patient‘s discharge. Thereafter, escalation of the opioid dose was only moderate during the eight months following opioid holiday.
It is not clear whether it is necessary to perform, during general anesthesia, antagonist-supported detoxification from opioids, since it may be the abstinence from opioids for a certain time rather than the presence of opioid antagonists that is critical to reestablish responsiveness to opioids. However, given the history of opioid addiction in our patient, ultra-rapid detoxification believed to be associated with a high rate of completed withdrawals and referrals for further treatment 20may have been the preferable withdrawal procedure.
After 2 weeks of drug holiday, radiotherapy was started but without any effects on tumor size or its progression. Although we cannot exclude that the rather small and apparently ineffective dose of radiotherapy may have contributed to analgesia following opioid holiday, it is unlikely to account for the excellent long-term pain reduction persisting for more than eight months despite extensive tumor progression.
In summary, therefore, when the analgesic effects of opioids decrease after long-term opioid administration resulting in insufficient treatment options, sensitivity of the opioid receptor system may be reestablished by antagonist supported detoxification from opioids and a drug holiday. Although rapid detoxification is not risk free, 21this technique may also be considered in selected patients with chronic pain who have become exceptionally tolerant to opioids but who do not have a history of drug addiction.