Why can a patient tolerate large doses of morphine but not small doses of clemastine, oxycodone or

Fråga: Why can a patient tolerate large doses of morphine but not small doses of clemastine, oxycodone or hydromorphon? What can be given as an alternative to morphine?

A 39-year-old woman with severe pain due to breast cancer and skeleton metastases is being treated with doses of morphine as high as 1000 mg daily intravenously without receiving sufficient effect. However, administration of low doses of Oxynorm (oxycodone) and Tavegyl (clemastine) treatment have caused fatigue and hydromorphone treatment has caused nausea. The patient is also being treated with Durogesic (fentanyl) 300 ug/h, Lanzo (lansoprazol) 30 mg daily, Tryptizol (amitriptyline) 75 mg daily, Arthrotec (diclofenac) 50 mg x3, Citodon (paracetamol, codein) 2 x3, Stesolid (diazepam) 10 mg x3 and Zoloft (sertraline) 1.5 tablet daily.

Sammanfattning: Decreasing response to morphine has been documented. In problems with inadequate analgesia and hyperalgesia, switching to methadone as the primary analgesic has been effective. Oxycodone is metabolised by cytochrome P450 isoenzyme 2D6 and the drug concentration could be increased if the present patient is a poor metaboliser. Hydromorphone, and clemastine are not metabolised to morphine and the drugs are known to cause adverse effects such as nausea and sedation.

Svar: Since opioids do not have any analgesic effect on idiopathic and neuropathic pain (1) it is important to classify the pain when choosing analgesic therapy. In the present case it might be difficult to distinguish the effect of one single drug considering the complicated therapy with several different opioids and analgesics. High doses of morphine during long-term therapy could be associated with increased levels of pain and cases of hyperalgesia, allodynia and myoclonus in cancer patients have been reported (2).

Effective treatment may be to switch the patient to methadone as an alternative analgesic (3). A prospective study was carried out during two years in 24 advanced cancer patients (4). After a switch to methadone, due to adverse effects, a clear improvement of the clinical condition was observed in most patients within one day. In another study 29 patients were stabilised on methadone after switching from morphine (5). Among them, 26 patients responded well to methadone. In addition, five patients whose pain was uncontrolled by oral morphine are documented (6). A pain relief was achieved in four of them by switching to oral methadone treatment. In one of the patients the pain control was so good that the patient stopped taking the methadone after discharge. The pain returned within 24 hours but total pain relief was restored when methadone treatment was restarted.

It has been suggested that an altered metabolism of morphine to morphine-3-glucuronide (M3G) may be the cause of the insufficient effect of morphine treatment, but to date this suggestion is unproven (3).

It is difficult to predict individual methadone doses when switching from morphine to methadone treatment due to large interindividual variation of methadone concentration explained by differences in metabolism and visual clearance of the drug. The equivalent dosage of methadone does not appear to be required and one tenth of the previous morphine dose has been reported (7).

Oxycodone is metabolized to oxymorphone in a reaction catalyzed by cytochrome P450 isoenzyme 2D6 (8). In a poor metabolizer of this enzyme the concentration of oxycodone should thus be enhanced, which might explain the adverse effects caused by oxycodone in the present case.

Hydromorphone is extensively metabolized to hydromorphone-3-glucuronide in a manner analogous to the metabolism of morphine to morphine-3-glucuronide (9). Fentanyl is known to be metabolized in the intestine and in the liver. N-dealkylation of fentanyl by cytochrome P-450 isoenzyme 3A4 is the predominant route in both organs (10). In conclusion, hydromorphone, fentanyl and clemastine are all individual chemical entities and their effects may thus be independent of the effect caused by morphine. Nausea, drowsiness, sedation and dizziness are well-known dose related adverse effects of hydromorphone (11), oxycodone (12) and clemastine (13). Sedating antihistamines, such as clemastine, may enhance the effects of CNS depressants including opioid analgesics (13). 1 Arner S, Gustafsson L, Hansson P, Kinnman E, Sollevi A, Sörensen J: Farmakologisk smärtanalys hjälp vid diagnostik och terapival. Lakartidnignen 1998; 24: 2824-8 2 Jacobsen LS, Olsen AK, Sjogren P, Jensen N-H: Morfininduceret hyperalgesi, allodyni og myoklonus. Ugeskr Laeger 1995; 157: 3307-10 3 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. p M229 4 Mercadante S, Casuccio A, Calderone L: Rapid switching from morphine to methadone in cancer patients with poor response to morphine. J Clin Oncol 1999; 17: 3307-12

5 Scholes CF, Gonty N, Trotman IF: Methadone titration in opioid-resistant cancer pain. Eur J Cancer Care 1999; 8: 26-9
6 Morley JS, Watt JWG, Wells JC, Miles JB: Methadone in pain uncontrolled by morphine. Lancet 1993; 342: 1243
7 Morley JS, Makin MK: Comments on Ripamonti et al. Pain 1997; 73: 114-115

8 Heiskenen T, Olkkola K, Kalso E: Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 1998; 64: 603-11 9 Wright A, nocente M-L, Smith M: Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation. Life Sciences 1998; 63: 401-11 10 Labroo R, Paine M, Thummel K, Kharasch E: Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 1997; 25: 1072-80 11 Drugline no 11362 (year 1994) 12 Micromedex Drugdex Drug Evaluation: Oxycodone 13 Parfitt K, editor. Martindale, The complete drug reference. 32nd ed. London: Pharmacol Press; 1999. P 399