Opioid Induced Pain in Hospice Patients: Hyperalgesia and Allodynia
Posted by Dr. Jim Joyner
Introduction to Opioid Induced Pain in Hospice Patients
Howard Hughes, the famous aviation pioneer, film-maker, and billionaire business- man became notorious in his later years for bizarre behaviors that were supposedly related to his addiction to opioids that he used for chronic intractable pain following a serious airplane crash decades earlier. It has been reported that he refused to cut his hair, trim his nails or brush his teeth for years. According to a recent book by Forest Tennant, MD; Howard Hughes & Pseudoaddiction (A brief medical tutorial on a saga of intractable pain) Mr. Hughes' avoidance behaviors were probably related to the severe pain that he experienced from performing these daily activities. The author suggests that he suffered from opioid induced allodynia.
Opioids have been implicated as a possible cause of paradoxical, exaggerated pain responses including allodynia and hyperalgesia. Allodynia is a significant painful response to a stimulus that is normally not painful such as light touch. Hyperalgesia is hypersensitive severe pain response to a stimulus that would normally produce only a very mild pain response. These conditions have been described as opioid induced neurotoxicity, a term that has also encompassed symptoms of myoclonus, seizures, and delirium associated with opioid use.
Hughes died in 1976. In his time these conditions were not recognized as possible opioid induced neurotoxicity, however, in the past several years more reports of the neuroexcitatory side effects of opioids have surfaced as health care providers have become more aggressive at pain management with opioids. Awareness of this unusual phenomenon has increased with the increasing use of opioids for chronic severe pain. These conditions are characterized by generalized, non-specific pain in patients who are receiving rapidly increasing doses of opioids, such as hospice patients. The pain will worsen despite increasing doses of the opioid drug. One of the hallmarks is that the pain becomes more diffuse, with a non-specific location, spreading well beyond the pre-existing sites of pain for which drug therapy was initiated. The patient's pain presentation changes to "pain all over" that doesn't make sense in terms of the underlying disease. The increase in pain is unexplained by increased cancer progression. Allodynia and hyperalgesia have been associated with other neurological symptoms such as myoclonus, seizures, and delirium although hypersensitive pain responses to opioids may occur without these additional symptoms.
Possible Mechanisms
There have been a number of possible mechanisms proposed as to how opioids may cause this paradoxical response. One important proposed mechanism is central nervous system sensitization due to opioid activation of the N-methyl-D-aspartate (NMDA) receptors and activation of intracellular messenger protein kinase C. These two changes result in increased excitability of the nerve cells. Another potential mechanism involves neuronal circuits in the brainstem where opioids may activate pathways that amplify pain signals at the level of the spinal cord.
The accumulation of specific opioid toxic metabolites has also been linked to these conditions. Evidence suggests that both morphine and hydromorphone have active metabolites that are responsible for allodynia and hyperalgesia (morphine-3-glucuronide and hydromorphone-3-glucuronide). Both of these active metabolites are eliminated by the kidneys and usually do not accumulate to produce toxicity, however, in the presence of renal impairment, or rapidly escalating high doses, the metabolites can accumulate and result in allodynia and hyperalgesia. Morphine and hydromorphone induced hyperalgesia is often accompanied by myoclonus, seizures, and/or delirium.
Management of Opioid Induced Pain in Hospice Patients
Although it may seem to be counterintuitive in the face of increasing severe pain, the appropriate intervention in the management of suspected opioid related hyperalgesia and allodynia is to reduce or discontinue the current opioid. Rotation to another opioid with less risk of neurotoxic effects is often an effective remedy. Methadone or fentanyl are appropriate choices for hospice patients who exhibit opioid induced pain on morphine or hydromorphone. Methadone and fentanyl do not have any active metabolites that can accumulate and contribute to neurotoxicity.
Methadone oral is much more cost-effective than the fentanyl patch since oral methadone is priced at approximately one-20th of the cost of an equivalent dose of the patch. Other interventions may include adding a non-opioid adjuvant analgesic medication such as dexamethasone (Decadron), gabapentin (Neurontin), or nortriptyline (Pamelor). Benzodiazepines such as lorazepam (Ativan) or midazolam (Versed) may be helpful in managing myoclonus or muscle rigidity which may accompany opioid induced pain.
Conclusion
The problem of opioid induced allodynia and hyperalgesia is difficult to recognize and interpret, especially in hospice patients. There are no estimates as to the frequency with which opioid induced allodynia or hyperalgesia occurs. It still may be a relatively rare side-effect; however, as hospice and health care providers aggressively manage severe chronic pain with strong opioids we will see an increase in the number of these cases. Any opioid may lead to a paradoxical increase in pain, although the majority of reports are due to morphine and hydromorphone.
Opioid induced pain should be considered in any hospice patient that exhibits increasing pain that does not respond to increasing doses of opioid, especially when the pain complaints become more diffuse, with a non-specific location, spreading well beyond the pre-existing sites of pain for which drug therapy was initiated. Hyperalgesia should be suspected whenever there is need for rapid escalation of opioid doses that is unexplained by disease progression. Opioid dose reduction or rotation to methadone or fentanyl should be considered as the primary method for management for hospice patients.