Adult Cancer Pain: Part 2 -- The Latest Guidelines for Pain Management

Laura A. Stokowski, RN, MS

Disclosures

December 06, 2010

In This Article

Pharmacogenetics in Pain Management

"If a patient is not having a response to a dose of pain medication, it's not necessarily malingering. It could be a different pharmacokinetic response to that drug in that patient. There is huge variability. One patient will get good relief from morphine, whereas another patient has horrible nausea and vomiting," comments Paice, explaining the increasingly recognized phenomenon of interindividual differences in metabolism of pain agents.

Clinicians have long known that patients can react differently to the same dose of a pain medication -- some having good and some having minimal pain relief. Patient response to opioids can be explained by many factors such as age, type of cancer, comorbidities, organ function, and other medications the patient is taking.[8]In addition, genetic differences in how drugs are metabolized by the liver is increasingly recognized as a key factor in interindividual and ethnic differences in clinical response.[9]Polymorphisms of the hepatic cytochrome P450 enzyme system might explain much of this variability by their effects on phase 1 metabolism of pain drugs such codeine, tramadol, hydrocodone, and oxycodone. Patients with a deficiency of one of these enzymes, CYP2D6, may not be able to convert codeine into morphine and therefore may get little or no analgesic effect from codeine.[4] As many as 7% of whites, and 2%-7% of blacks are poor metabolizers of CYP2D6-dependent opioids.[10]

In addition to therapeutic failure, adverse drug reactions can occur as a result of inhibition or induction of P450 enzymes by other drugs the patient is receiving concurrently with pain medication.[11] The CYP34A enzyme is the primary metabolizer of fentanyl and oxycodone.[11] Therefore, these 2 drugs can interact with substances that either induce or inhibit the CYP34A enzyme. Administration of CYP3A4 substrates or inhibitors (such as bergamottin, found in grapefruit juice) can increase opioid concentrations, thereby prolonging and intensifying analgesic effects as well as adverse opioid effects, such as respiratory depression. Administration of CYP3A4 inducers (such as cafestol, found in unfiltered coffee) can reduce analgesic efficacy.[12] Consequently, when patients report a lack of analgesic benefit, or excessive side effects, it is important to investigate what else patients are consuming that might be interacting with prescribed pain medication.

The concept of interindividual variation in metabolism receives more attention in NCCN v.2010, particularly the possible influence of cytochrome P450 enzymes on cancer pain management. Drug-drug interactions involving co-analgesics and cancer treatment are provided as an example of these pharmacogenetic differences.

Antidepressants are often used as co-analgesics to reduce the dose of opioids in patients with neuropathic pain. Several antidepressants are known inhibitors of hepatic drug metabolism via inhibition of cytochrome P450 enzymes, especially CYP2D6. Tamoxifen, often used in the treatment of breast cancer, undergoes extensive hepatic metabolism, and inhibition of CYP2D6 reduces the production of tamoxifen metabolites, potentially limiting the drug's tumor-fighting effectiveness. The risk for breast cancer is increased in patients taking tamoxifen and some selective serotonin reuptake inhibitors concomitantly, especially some of the moderate-to-potent CYP2D6 inhibitors such as paroxetine or fluoxetine. A preferred choice of selective serotonin reuptake inhibitor for a patient on tamoxifen is an antidepressant that produces mild CYP2D6 inhibition, such as sertraline, citalopram, venlafaxine, or escitalopram.[2]

Similarly, the pain medication propoxyphene is an inhibitor of CYP2D6 and may increase the risk for recurrence of breast cancer in patients taking tamoxifen. For this reason (among others), propoxyphene is not recommended in the management of adult cancer pain.

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