In 2006, approximately 26% of Americans, or 76.5 million people, older than 20 years of age reported that they had suffered pain lasting more than 24 hours.1 Of those suffering from pain, 42% reported that the pain lasted longer than one year.¹
The use of opioids for chronic non-malignant pain has become increasingly accepted. Based on the World Health Organization analgesic ladder for pain, opioids should be instituted for pain that is classified as moderate to severe or when non-opioid analgesics have failed to achieve optimal pain control.² Opioids must be carefully managed for all patients to effectively control pain while minimizing adverse effects.
Renal Insufficiency
An estimated 37 to 50% of hemodialysis patients experience chronic pain, with 82% of that pain classified as moderate to severe.³˒⁴ Patients may suffer from pain related to their primary renal condition, but often other factors contribute to their reports of pain. Patients with renal insufficiency experience pain that is multi-factorial, since co-morbidities such as vascular diseases and diabetes may lead to neuropathic pain, and arthritis may cause musculoskeletal pain.⁴
Opioids are often needed for effective pain control for these patients. The absorption, metabolism, and renal clearance of opioid analgesics are often quite complex requiring frequent dose adjustments and medication changes.³˒⁴ The properties of the parent drug and its metabolites must be considered when selecting an opioid analgesic for this patient population.⁴˒⁵ For example, meperidine is metabolized in the liver to the metabolite normeperidine—a CNS excitotoxin—and then excreted by the kidneys. In cases of renal insufficiency, normeperidine accumulates and may cause anxiety, tremors, myoclonus, and generalized seizures and is therefore not recommended for use in renal insufficiency.⁶ Unfortunately, the data on the pharmacokinetic and pharmacodynamic properties of some opioids is limited and sometimes conflicting—presenting additional challenges for clinicians.⁴ For example, oxymorphone—the only active metabolite of oxycodone—was found to have no pharmacodynamic effects in subjects with normal renal function but the cumulative effects of this metabolite in renal failure are not known.⁷ The author reported CNS toxicity and sedation with normal doses of oxycodone with renal failure,⁷ so that clinical experience is often necessary to determine the most appropriate opioid analgesics for patients.
Glomerular filtration rate (GFR) is one measure of the elimination of opioid analgesics from the body. The chemical properties of opioids (weak organic bases) may be altered by urine pH thus affecting the relationship between GFR and renal elimination. Nevertheless, GFR is sometimes used by clinicians to assist with opioid analgesics dose adjustments in patients with renal insufficiency.⁷ For example, the dose of morphine may be initiated at 75% of the normal dose for patients with a GFR of 20-50 mL/min.⁷
Table 1 provides general recommendations for common opioid use in patients with renal insufficiency.
Hepatic Insufficiency
Many patients suffering from liver failure may experience pain. The pain may have various causes, including pain from the stretching of the liver capsule or bone pain caused by metastatic liver cancer.⁸ Therefore, treatment with opioid analgesics is often needed for effective control of moderate to severe pain.
As the liver is primarily responsible for the metabolism of opioid drugs to their metabolites, the pharmacokinetic and pharmacodynamic properties must be carefully reviewed prior to initiating these agents in this patient population.5 Oxidation is the major metabolic pathway of most opioids with the exception of morphine and buprenorphine, and oxidation is decreased in patients with hepatic cirrhosis.⁸ This may result in decreased drug clearance, increased oral bioavailability, and decreased first-pass metabolism.⁸ These factors must be considered when selecting and dosing opioid analgesics.⁸ Morphine, although metabolized through glucoronidation, has also been shown to have decreased clearance and increased oral bioavailability in patients with liver cirrhosis.⁹
Decreases in drug metabolism with liver insufficiency can therefore lead to accumulation of the drug in the body with repeated administration and long-term use. Therefore, lower doses and longer administration intervals may be warranted.⁹
Table 2 provides general recommendations for common opioid use in patients with liver insufficiency.
Geriatric Patients
The incidence of painful conditions is quite high in geriatric patients yet their pain is often undertreated. The American Geriatric Foundation reports that approximately 25-50% of community-dwelling elders can expect to suffer pain and 71-83% of institutionalized elders report some type of pain.¹ Therefore, geriatric patients represent another challenging population for pain management clinicians. Economic, emotional, and physiologic issues must all be carefully considered in this population. The assessment and management of pain in the elderly may often be difficult. Loss of sensory neurons may result in altered perception of pain, and pain assessment is often impacted by co-morbid conditions such as dementia.¹⁰
Altered pharmacokinetic and pharmacodynamic profiles pose an additional challenge for effective treatment of chronic pain in the elderly. Pharmacokinetic changes include delayed elimination of drugs due to hepatic and renal insufficiency, reduced receptor sites for drug binding, and reduced volume of distribution.¹⁰ There is often a narrow therapeutic index for opioid analgesics related to hepatic and renal insufficiency and an increased sensitivity to CNS drugs and so adverse effects must be carefully monitored.¹⁰˒¹¹ For example, in older patients, a longer duration of action has been observed following morphine administration due to a prolonged elimination of the drug from the plasma.⁶
The use of opioid analgesics for geriatric patients with moderate to severe, chronic, non-malignant pain is becoming increasingly accepted.¹² It is important to recognize that in addition to the possibility of an increased sensitivity to CNS agents, geriatric patients should also be monitored for drug-drug and drug-disease interactions prior to the initiation of an opioid analgesic.¹¹ For patients older than 70 years of age, doses should be initiated at 25 to 50% of the adult recommended started dose then slowly titrated upward to minimize adverse effects.⁶
Based on the unique challenges of geriatric patients, general recommendations for opioid analgesic selection are available. Opioids that should be avoided in the elderly include meperidine and propoxyphene. The accumulation of normepederine, the metabolite of meperidine, may cause CNS toxicity and lead to adverse effects including increased sedation and falls in the elderly.¹⁰ Propoxyphene may have questionable benefits over aspirin or acetaminophen therapy alone and accumulation of its metabolite, norpropoxyphene, may lead to an increased risk of adverse effects such as dizziness, ataxia, neuroexcitatory effects, and cardiotoxicity; e.g., arrhythmias.¹⁰˒¹¹˒¹² Opioids that may be initiated with careful monitoring include morphine and fentanyl. There is a risk of accumulation of the metabolite of morphine in renal insufficiency, so patients should be carefully monitored for adverse effects. Dosing should “start low and go slow” in frail elderly.¹⁰ Transdermal fentanyl should be used with caution in the elderly and should not be initiated in opioid naïve patients.¹² The long and variable half-life observed with methadone limits its potential use in this population.¹¹˒¹² If methadone is used, careful monitoring by an experienced clinician is recommended, as the short analgesic effect may cause increased doses to be prescribed leading to a risk of respiratory depression.¹² Hepatic and renal function must be carefully monitored in this population, and the recommendations applicable to hepatic/renal impairment may also be useful when selecting opioids in the geriatric population.
| Drug Name | Recommendation | Notes |
| Meperidine | Not Recommended | Accumulation of toxic metabolite, normeperidine, may cause CNS toxicity.³˒⁴ |
| Codeine | Not Recommended | Accumulation of active metabolites in renal failure.5 Case reports of toxicity and serious adverse effects which can be delayed.⁴˒⁷ |
| Propoxyphene | Not Recommended | Accumulation of parent and metabolites may cause CNS and cardiac toxicity.⁵ |
| Morphine | Use cautiously | Metabolite morphine-6-glucuronide, a more potent analgesic, may accumulate causing more sedation.⁴ If morphine must be used, it is recommended to use cautiously and adjust dose appropriately.⁵ |
| Oxycodone | Use cautiously | Insufficient evidence available for strong recommendation.⁴˒⁷ Reports of accumulation of both parent compound and active metabolite, free oxymorphone, leading to CNS toxicity and sedation.³˒⁵˒⁷ |
| Hydromorphone | Use cautiously | Metabolite, hydromorphone-3-glucuronide can accumulate and cause CNS toxicity.⁴˒⁵˒⁷ Careful monitoring of patients on dialysis and avoid use in patients with GFR < 30mL/min.³ |
| Fentanyl | Appears safe | Some reports of parent compound accumulating in renal failure, but no increase in adverse effects.⁷ The metabolites are considered inactive.⁴ A dose reduction may be necessary.⁵ With long term use, careful monitoring of pharmacodynamic effects is advised.⁷ |
| Methadone | Appears safe | Recommended to be used only by experienced clinicians.⁴ No active metabolites are formed and limited plasma accumulation of the drug observed in renal failure.³ Dose reduction may be necessary in severe renal failure.⁷ |
| Drug Name | Recommendation | Notes |
| Meperidine | Not Recommended | Accumulation of toxic metabolite, normeperidine, may cause CNS toxicity.⁵˒⁸˒⁹ |
| Codeine | Not Recommended | Impaired coversion of codeine to the active compound, morphine, in the liver to be active.⁵˒⁸ |
| Propoxyphene | Not Recommended | Several reports of liver toxicity reported due to metabolite, dextropropoxyphene.⁸ |
| Morphine | Use cautiously | Recommended to decrease frequency of administration and dosage because of decreased clearance and increased t1/2 and oral bioavailability.⁹ |
| Oxycodone | Use cautiously | Risk of accumulation of parent drug due to decreased conversion to metabolites and decreased elimination.⁵˒⁸ Recommended to reduce dose by 1/2 to 1/3 of the usual amount and avoid in severe cirrhosis.⁵ |
| Hydromorphone | Use cautiously | Risk of accumulation of parent drug due to decreased conversion to metabolites and decreased elimination.⁵ Recommended to decrease dose by 50% of the usual amount.⁵ |
| Fentanyl | Appears safe | Pharmacokinetics were not altered in patients with cirrhosis.8,9 With continued use, recovery time after termination of infusion may be longer.⁹ |
| Methadone | Not Recommended | Risk of accumulation with severe liver disease.⁵˒⁹ |
Conclusion
Opioid analgesics can present many challenges to clinicians, and close attention must be paid to special populations requiring opioid therapy for pain control. Careful monitoring of all chronic pain patients is necessary to effectively manage pain while minimizing the potential for adverse drug effects. Individualized patient selection of opioids is important as pharmacokinetic and pharmacodynamic properties must be accounted for prior to opioid initiation. It is important to monitor for all adverse effects associated with these agents—including respiratory depression, sedation, constipation, and nausea and vomiting—and provide treatment when necessary.
Acknowledgement
The author wishes to acknowledge the assistance of Dr. Charles D. Ponte in the preparation of this manuscript.