The Use of Opioids in Palliative Medicine

Opioids and Pain in Palliative Care

From Medscape Nurses

Opioid therapy is the cornerstone of management of severe chronic pain in the field of palliative care medicine. Medical and societal philosophy evolved during the 1960s and 1970s to accept the use of opioids in the treatment of both malignant and nonmalignant pain. A wide variety of clinicians prescribe opiates, ranging from palliative care and pain management specialists to primary care clinicians. Millions of patients now have their suffering lessened by this newer application of an old remedy.
In spite of the long established history of opioid therapy and its widespread use today, clinical problems in the proper use of opioid therapy remain prevalent. 
These problems can be divided into 2 main categories:
(1) errors in prescribing opioids, and (2) opioid toxicity.

Errors in Opioid Prescribing

Various medical organizations, including the Agency for Health Care Policy and Research, the World Health Organization, and the American Pain Society, have developed consensus guidelines to educate clinicians and to promote the rational use of opioids. Nevertheless, clinical studies continue to demonstrate that errors in opioid prescribing are common.
At the Annual Assembly of the American Academy of Hospice and Palliative Medicine and Hospice and Palliative Nursing Association in January 2005, Philip Shaheen, MD, and colleagues, from the Harry R. Horvitz Center for Palliative Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, addressed this topic in a prospective study.^[1] Of 132 patients with cancer-related pain, 76% experienced errors in opioid dosing. Shaheen chose to divide these errors into categories: (1) errors in dosing strategy (which represented over 80% of all errors); (2) errors in opioid conversion/rotation; (3) errors in titration; and (4) misuse or failure to use adjuvant analgesics. The errors in dosing strategy involved a variety of problems, including undertreatment of pain, undertreatment of side effects, incorrect dosing intervals, and the use of multiple opioids simultaneously. They concluded that errors are common, despite the existence of opioid dosing guidelines.

Failure to Prescribe Around-the-Clock Opioids for Constant Pain

Others have made similar observations regarding common errors in opioid prescribing.^[2] Perhaps the most common error is the use of opioids on an as-needed basis, rather than around the clock on a regularly scheduled interval; this is especially true when the patient has constant pain rather than incident or activity-related pain. A similar error is the reliance upon short-acting opioids when long-acting opioids would be more effective in creating more stable serum levels. Using incorrect dosing intervals also results in fluctuating serum levels. The experts suggest that with too long dosing intervals, a component of "mini-withdrawal" is added, resulting in increased pain.

Failure to Prescribe Short-Acting Rescue Opioids

Even when opioids are prescribed on an around-the-clock schedule, clinicians may neglect to prescribe short-acting opioids for transient flares of breakthrough or incident pain. Rescue dosing strategies vary. The every-4-hour dose of a short-acting opioid may be offered hourly as a rescue dose, or 5% to 10% of the 24-hour total dose may be offered hourly for breakthrough pain.

Errors in Dose Titration

Opioid dose adjustments are usually made in 1 of 2 ways. The dose of rescue medication given over a 24-hour period may be added to the around-the-clock dose and used to calculate the new 24-hour dose of opioid; or the scheduled dose may be increased by 25% to 100%, depending on the severity of the pain and the patient's response to previous dose titration.
Errors in dose titration also arise when breakthrough or end-of-dose failure pain is not distinguished from incident or activity-related pain. Nonincident pain is best treated by gradually increasing the around-the-clock, scheduled opioid dose, as described above. Incident pain that is brought on by a specific activity is best treated with a pre-emptive dose of short-acting opioid given in advance of the activity. Do not titrate the around-the-clock opioid dose for incident pain! This may result in oversedation or other unwanted side effects.

Use of Multiple Opioids and Formulations

Using multiple opioids of the same or similar class is also a common error in clinical practice. Although there are theoretical benefits to opioid polypharmacy, based on the differing interaction with opioid receptors, benefits are outweighed by the drawbacks in most cases. Multiple opioid medications increase treatment complexity, cost, and dosing errors while decreasing patient compliance. Most importantly, using multiple opioids makes evaluation of toxicity and side effects almost impossible. The one common exception to this rule is the use of less expensive short-acting opioids for breakthrough pain with transdermal fentanyl.

Incorrect Conversions and Rotations

Conversion and equianalgesic tables are usually based on single doses of drugs or drugs at steady state and may not accurately represent the dose needed when titrating uncontrolled pain. Many experts recommend decreasing the "equianalgesic" dose by 25% to 50% when rotating to a new opioid, to account for incomplete cross-tolerance. Individual patient characteristics must also be taken into consideration, including pain level, side effects, and frailty. It is recommended that opioid route conversions in hospitalized patients be followed for at least 24 hours before discharge, noting that the absorption of oral morphine is highly variable.
Opioid rotation was detailed in another presentation.^[3] Bassam Estfan, MD, and associates, from the Harry R. Horvitz Center for Palliative Medicine, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, sought to define the frequency of opioid rotation in advanced cancer patients and to define the reasons for rotation. A total of 195 consecutive cancer patients were followed by the palliative medicine service over a 2-month period. A total of 132 of these patients had pain; 54 of the 132 (39%) were rotated. Thirteen had a second rotation, 4 a third, and 1 a fourth rotation. Ineffective pain control was the most common reason for opioid rotation (31%), followed by opioid related side effects (25%), or both (21%). The most common opioids before rotation were oxycodone (48%) and morphine (27%). Most rotations were to morphine (54%) followed by methadone (31%). They concluded that opioid rotation is common in managing the pain of patients with advanced cancer, occurring in almost 40% of their patients. The reasons for rotation are usually for ineffectiveness, side effects, or both. Most patients are rotated once, but almost a third require sequential rotations.

Failure to Recognize and Manage Opioid-Related Side Effects

Side effects were unrecognized or inadequately treated in 15% of the patients in the Shaheen study.^[1] Although constipation is the most frequent and persistent side effect of chronic opioid therapy, opioid-related neurotoxicity, especially sedation and delirium, are often treatment-limiting in patients with severe pain and received specific consideration at the Assembly in New Orleans.

Opioid Neurotoxicity

Daniel Thwaites, MD, and colleagues, from Community Hospice, Inc., Modesto, California, presented data reviewing the incidence of neuroexcitatory symptoms during continuous hydromorphone infusion.^[4] They retrospectively reviewed the charts of 48 terminally ill hospice patients who received continuous parenteral hydromorphone for pain control, searching for agitation, myoclonus, and seizures. Agitation was associated (P < .01) with known metastatic disease. Agitation, myoclonus, and seizures were independently associated with the maximal dose (P < .05, P < .001, and P < .05, respectively) and with the duration (P < .01, P < .05, and P < .01, respectively) of continuous parenteral hydromorphone. The researchers suggested that the metabolite hydro-morphone-3-glucuronide may be responsible for the increase in neuroexcitatory symptoms.
Neal E Slatkin, MD, DABPM, and Michelle Rhiner, MSN, RN, NP, from City of Hope National Medical Center, Duarte, California, discussed opiate-induced neurotoxicity.^[5] They described the progression of neurologic and psychological toxicity from opioids as resulting in a continuum of symptoms including sedation, hallucinations, myoclonus, seizures, and cognitive dysfunction. Sedation, the most commonly seen symptom of toxicity, is considered the "tip of the iceberg" leading toward delirium and obtundation.
When sedation occurs, other causes need to be excluded, and one can wait 7 to 10 days to allow tolerance to develop. One should also discontinue other sedating adjuvant medications. If symptoms persist, opioid dose reduction or opioid rotation to an alternate drug or another route of administration is the next step.
If sedation persists, or if there is reluctance to reduce the opioid dose, psychostimulants may be used to counteract the opioid-induced sedation. It should be noted that the use of these medications in this manner is not approved by the US Food and Drug Administration, and is therefore considered "off-label" prescribing. Methylphenidate (Ritalin) and dextroamphetamine (Adderal) block the reuptake of norepinephrine and dopamine in presynaptic nerve terminals to increase alertness. Modafinil (Provigil) may also be used, but it is expensive and its mechanism of action is unknown. Dr. Slatkin discussed the use of donepezil (Aricept) as a cost-effective stimulant (also an off-label use), starting with doses of 2.5 mg in the morning, gradually increasing to 5 mg in the morning, with a maximum dose of 5 mg in the morning and 5 mg midday. Donepezil is an acetylcholinesterase inhibitor and appears to work by counteracting the opioid-induced reduction in acetylcholine within the brain. Dr. Slatkin found that 42% of his patients responded to donepezil, and 58% did not.
Delirium can complicate opioid therapy. Disorientation with impaired memory and language develops with a subacute onset and fluctuating course. Hallucinations and delusions often occur early in opioid-related delirium. The role of dehydration compounding the accumulation of neurotoxic metabolites is controversial, but Dr. Slatkin reminded us that symptoms may be controlled with hydration alone. Generally haloperidol (Haldol) or other neuroleptics are the treatment of choice. Benzodiazepines should be used only with caution. Slatkin commented, "The number one cause of delirium is the indiscriminate use of lorazepam (Ativan)."
When evaluating the patient with delirium, be sure to consider nonopioid causes, including infection, electrolyte imbalance, and other potentially neurotoxic medications commonly used as adjuvants, such as the antidepressants and anticonvulsants. Discontinue all benzodiazepines. Consider a trial of hydration.
Opioid-induced myoclonus is often a sign of evolving delirium. Risk factors include dehydration and other medications (eg, selective serotonin reuptake inhibitors, dopamine antagonists, and nonsteroidal anti-inflammatory agents [NSAIDs]). NSAIDs are thought to produce mild renal insufficiency and decrease opioid and metabolite excretion. Treatments to consider are hydration, opioid rotation, and GABA agonists such as clonazepam and baclofen.
Seizures are a rare complication except with meperidine (Demerol). They may result from hypoxia or respiratory depression.

New Strategies for Pain Control

Parag Bharadwaj, MD, and Maria V. Danilychev, MD, from San Diego Hospice, California, presented a case of central post-stroke pain syndrome treated with parenteral lidocaine.^[6] When hydromorphone was rapidly titrated to 24 mg/hour without symptom relief, they began lidocaine 2 mg/kg over 20 minutes, followed by 1 mg/kg/hour continuous infusion. The lidocaine produced complete pain relief and the hydromorphone dose was decreased by 50%, with lessening of somnolence and improved quality of life until the patient's death 2 weeks later.
Slatkin and Rhiner reviewed a series of 11 patients (10 of whom were evaluable) who received intrathecal phenol caudal blocks for control of severe rectal and perineal pain, and painful lumbosacral plexopathies.^[7] The oral morphine equivalents (OMEq) before the procedure ranged from 294-8100 mg (mean dose 1896 mg). Phenol 6% in glycerin was used in 9/10 patients, the average injection being 0.8 mL. The target rectal/perineal pain was reduced in all patients. Lumbosacral neuropathic pain responded less well. OMEq fell on average by 37% in all patients, sedation improved in 7 patients, and functional activity improved in 5 patients.

Summary

Errors in opioid prescribing are common and can be avoided by remembering to avoid the pitfalls:

 using as-needed dosing for continuous pain, failing to treat breakthrough and incident pain, and using more than one opiate at a time.
Opioid neurotoxicity is a dose-limiting side effect in many patients that can be minimized by accurate prescribing, careful opioid rotation, and attention to the patient's general condition, other medications, and prudent use of adjuvant mediations or therapies, including local anesthetic procedures.

References

1. Shaheen P, Estfan B, Davis MP, Walsh TD, LeGrand SB, Lagman RL. Errors in opioid prescribing: a prospective survey. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Abstract 729.
2. LeGrand SB, Davis MP, Lagman RL, Walsh TD, Shaheen P. Common errors in opioid prescribing. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Session 518.
3. Estfan B, Shaheen P, Walsh D, Davis MP, LeGrand SB. Opioid rotation in cancer pain: a prospective longitudinal study. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Abstract 728.
4. Thwaites D, McCann SE, Broderick P. Hydromorphone neuroexcitation. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Session 506.
5. Slatkin NE, Rhiner M. Opiate induced neurotoxicity in the palliative care patient. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Session 302.
6. Bharadwaj P, Danilychev MV. Central post stroke syndrome treated with parenteral lidocaine. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Abstract 722.
7. Slatkin N, Rhiner M. Analgesic effects of neurolytic "saddle blocks" in patients with advanced pelvic malignancies and severe pain. Program and abstracts of the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association Annual Assembly; January 19-23, 2005; New Orleans, Louisiana. Abstract 733.