Extra Care Required When Making Opioid Conversions

 VIENNA, Austria—Since most palliative care pain patients will require one or more changes in drugs due to inadequate pain relief, “physicians caring for terminally ill patients must be familiar with multiple drugs and routes of delivery,” Eduardo Bruera, MD, chairman of the Pain Department, M.D. Anderson Cancer Center, said at the 9th World Congress on Pain, sponsored by the International Association for the Study of Pain.

Dr. Bruera, who chaired a session on cancer pain and palliative care, discussed in particular the use of oxycodone and methadone in this setting. These two older opioid agents are being increasingly used in cancer pain, and Dr. Bruera pointed out why physicians may need to take extra care when converting patients to or from these opioids.

Oxycodone has been used as both short-acting and sustained-release oral preparations as well as a parenteral preparation for management of cancer pain, Dr. Bruera said. Oxycodone was found to have about 50% greater potency compared to morphine, according to studies by Heiskennan, so that a 30 mg dose of oral morphine sulfate would be equivalent to approximately 20 mg of oral oxycodone. Dr. Bruera noted, however, that the conversion ratio reported in other studies ranges from 1:1 to 1:2.

In a double-blind, randomized, crossover trial comparing sustained-release morphine sulfate every 12 hours with sustained-release oxycodone every 12 hours at a 3:2 ratio, Dr. Bruera found similar pain control, sedation, and other side effects with the two agents. Fewer rescue medications were needed at night with use of both sustained-release agents, compared with use of short-acting agents.

Oxycodone, however, must be biologically converted by the hepatic enzyme cytochrome P450 2D6 into its active metabolite, oxymorphone, to provide analgesia. Approximately 10% to 15% of the population have genetically low concentrations of this enzyme, which can also be inhibited by such drugs as fluoxetine (Prozac) or quinidine.

James Clearly, MD, demonstrated that animals with low levels of this enzyme required a 10-fold increase in oxycodone dose in order to have the same effects.

Whether this effect occurs in humans has not yet been determined. However, Dr. Bruera presented the case of a patient who had inadequate pain relief with oxycodone for cancer-related pain due to bone metastases. Over 10 days, the oxycodone dose was escalated without significant improvement in pain.

When switched to an equianalgesic dose of hydromorphone, the patient developed symptoms of opioid toxicity requiring reversal with naloxone. This implied that the patient needed a lower dose of hydromorphone, a drug that, unlike oxycodone, does not require bioconversion to have analgesic properties.

Methadone Conversions

Methadone, a relatively inexpensive opioid for chronic pain, does not have active metabolites. It is well absorbed by the oral route and exhibits both µ-opioid and NMDA (N-methyl D-aspartate) receptor antagonism effects. However, it has a relatively long half-life with significant interindividual variability, which can result in accumulation and toxicity.

Dr. Bruera found that patients could be changed from morphine sulfate or hydromorphone to methadone with acceptable analgesia and side effects. However, methadone was significantly more potent than previously expected, and the potency and conversion ratios were even greater for patients changed from higher doses of other opioids to methadone.

For instance, for oral morphine doses from 30 to 90 mg/day, studies showed that the dose conversion ratio was 4:1. For morphine doses from 90 to 300 mg/day, the ratio when switching to methadone was 8:1, and for oral morphine doses higher than 300 mg/day, the ratio for conversion to methadone was 12:1. However, there tends be a significant amount of interindividual variability. This implies that there is little cross tolerance between methadone and other opioids, he said.