Dr. David Lussier, Institut universitaire de gériatrie de Montréal, University of Montreal Division of Geriatric Medicine and Alan-Edwards Centre for Research on Pain, McGill University, Montreal.

Disclosure: In his capacity as a speaker and consultant, Dr. Lussier receives honoraria from Janssen-Ortho, Merck Frosst Canada, Pfizer Canada and Purdue Canada.

Pain is a frequent problem in older adults. In community-dwelling older adults, its prevalence is estimated at 50% to 75% and it is the most frequently reported symptom. Chronic pain is associated with numerous detrimental impacts on functioning and quality of life, including decreased autonomy to perform activities of daily living, sleep and cognitive impairments, decreased appetite with weight loss, anxiety, depressive symptoms, social isolation, and increased health-care utilization and costs. Inadequate pain relief can also lead to postoperative delirium in patients with hip fracture, for whom severe pain and insufficient opioid analgesia have been reported to be major risk factors for delirium.

Pain is unfortunately often undertreated in older patients, whether it is acute (e.g., emergency room, postoperative) or chronic, and especially in long-term care institutions. Patients who are very old or have cognitive impairment are also at higher risk of not being treated adequately. Even though pain management is often complicated by the presence of several comorbidities (e.g., renal failure, cognitive impairment) and polypharmacy, it is usually possible to obtain good pain control in older patients when using a combination of non-pharmacological and pharmacological approaches, adapted to older patients’ specific needs.

Non-pharmacological treatment
Non-pharmacological approaches should always be part of the therapeutic plan for pain management in older patients, since they are often effective in providing pain relief and are devoid of adverse effects frequently encountered with medications. A tailored physical therapy and rehabilitation program is also essential to prevent further deconditioning and allow patients to recover their functional autonomy and ambulation.

Pharmacological treatment

Age-related pharmacological changes
Aging is associated with several pharmacological changes that modify pharmacokinetic and pharmacodynamic properties of analgesic agents, and should therefore be considered when prescribing an analgesic to an older patient.

Oral absorption is unchanged but can be slower, which can delay the analgesic onset of an oral analgesic. Liver metabolism changes include decreased first pass, which can increase the bioavailability of medications with a high extraction coefficient (e.g., morphine) and decrease activation of pro-drugs (e.g., codeine). Phase 1 reactions (oxidation, reduction, hydrolysis) are reduced, while phase 2 reactions (conjugation, synthesis) are unchanged. Older persons are mostly slow acetylaters. Studies on cytochromes have yielded different results, but there does not seem to be any significant difference.

The most significant changes relate to distribution volume and renal clearance. Since aging is associated with decreased total body water and increased fat mass, hydrophilic drugs have a smaller distribution volume (which decreases half-life and increases plasmatic concentration), while lipophilic drugs have a larger distribution volume (which increases half-life and decreases plasmatic concentrations). Lipophilic drugs (e.g., fentanyl, methadone) should therefore be prescribed with caution in older patients, given a prolonged half-life. Finally, aging is almost always accompanied by a decreased glomerular filtration and renal function, which favours accumulation of renally excreted drugs (e.g., codeine, morphine).

When prescribing an analgesic to an older patient, it is important to know the pharmacologic properties of the drug in order to select the most appropriate one and administer the appropriate dose.

Acetaminophen
Acetaminophen is recommended as first-line therapy for mild to moderate pain, especially of musculoskeletal origin (AGS 2002). It is well-tolerated when used appropriately. Its half-life might be mildly increased in older frail patients, so it could be administered every six rather than every four hours. The maximum daily dose should not exceed 2.6 g because liver toxicity can occur with lower doses than for younger patients.

Non-steroidal anti-inflammatory drugs (NSAIDs)
In older patients, NSAIDs should only be used in inflammatory conditions not responding to acetaminophen. Their superiority over acetaminophen is unclear for non-inflammatory musculoskeletal pain (e.g., osteoarthritis) and they are not effective for neuropathic pain. However, they are associated with significant toxicity and frequently cause potentially serious adverse effects (gastric, renal, cardiovascular). When used, renal function should be monitored, with frequent re-evaluation of their indication, efficacy and tolerability.

Topical NSAIDs can be used safely because of the absence of significant systemic absorption.

Tramadol
In addition to being a weak opioid agonist, tramadol inhibits the reuptake of serotonin and noradrenaline, with both mechanisms contributing to its analgesic activity. Because of this dual action, it can provide better pain control and might be advantageous for neuropathic pain. It has been well-studied in older patients, in whom it seems effective and well-tolerated, without any significant changes of its pharmacological properties. In older patients, it is better to initiate treatment using the short-acting formulation (in combination with acetaminophen) and change to a long-acting formulation after ensuring good tolerability.

Opioids
As in younger patients, opioids are indicated for moderate to severe pain, or pain not responding to non-opioid analgesics. When used appropriately, they can often provide adequate pain relief without significant adverse effects, even in very old patients.

There are very few data on the pharmacological properties of opioids in older patients. Therefore, the choice of the opioid mainly depends on the prescriber’s experience, as well as the patient’s comorbidities and other medications. It has, however, been shown that older patients often require lower and less frequent doses of opioids to obtain similar pain relief. Because of their higher sensitivity to adverse effects, it is important in older patients to initiate therapy with low doses and slowly titrate up based on analgesic response and tolerability.

Since morphine is renally excreted, decreased renal function, frequently encountered in older patients, can cause accumulation of morphine and its active metabolites morphine-3-glucuronide and morphine-6-glucuronide, which can lead to adverse effects. Morphine is therefore not the best opioid for older patients, especially in presence of renal insufficiency.

Codeine should also be avoided for these reasons, as well as because it is a pro-drug that requires transformation to its active metabolites, morphine and norcodeine, via the cytochrome CYP2D6. In 10% to 20% of the population, who cannot transform it in its active metabolites, codeine will not exert any analgesic activity. The same problem can occur in patients receiving inhibitors of CYP2D6 (e.g., selective serotonin reuptake inhibitors) or CYP2D6 substrates of higher affinity than codeine. Clinical experience also suggests codeine is associated with a higher frequency of nausea, confusion and constipation than other opioids.

Oxycodone and hydromorphone are often recommended in older patients. Oxycodone and its metabolites accumulate less in renal insufficiency, while metabolites of hydromorphone do accumulate but possess only weak opioid agonist activity, so are less likely to cause adverse effects.

Some opioids should not be used in older patients. Meperidine and its metabolite, normeperidine, accumulate with repeated use, especially in presence of renal insufficiency. They are stimulants of the central nervous system, which increases risks of falls, sedation, agitation and confusion, and decreases seizure threshold. Propoxyphene and pentazocine should also be avoided because they also accumulate in renal failure and are associated with a high frequency of cognitive adverse effects.

While older patients with chronic constant pain benefit from long-acting or sustained-release opioids as much as younger ones, it is usually better to first prescribe several daily doses of a short-acting opioid on a regular basis, and switch to an equianalgesic dose of a long-acting or sustained-release opioid when good tolerability has been assured. While transdermal fentanyl can be useful in older patients with dysphagia or those not responding to another opioid, it should never be used in opioid-naive older patients, as the lowest available dose (12 mcg/h) is much too high. Because of its high lipophilicity, fentanyl also tends to accumulate in older patients, especially if obese. Finally, age-related cutaneous changes make its absorption less predictable.

Methadone is a useful opioid in patients with unrelieved pain despite high doses of opioids, as well as those with cancer pain or some types of neuropathic pain. However, because of its long and variable half-life, as well as its lipophilicity, it should be used with caution in older patients.

Adjuvant analgesics
As for opioids, there are very few data on analgesic activity and tolerability of adjuvant analgesics in older patients. It is, however, clear that tricyclic antidepressants, often recommended as first-line therapy for neuropathic pain, are associated with several potentially serious adverse effects in older patients, mainly because of their anticholinergic effects (e.g., sedation, confusion, urinary retention) and cardiac toxicity.

When using a tricyclic antidepressant, secondary amines (nortriptyline, desipramine) should be favoured over tertiary amines (amitriptyline) because they are better tolerated. For neuropathic pain, it is much preferable to use the anticonvulsants gabapentin and pregabalin, which are much better tolerated and possess analgesic activity similar to tricyclic antidepressants. Efficacy and tolerability of pregabalin have been reported specifically for older patients, and appear to be similar to younger patients, if initiated at a very low dose (e.g., 25 mg HS or bid) and titrated progressively.

For older patients with chronic pain and concomitant depression or anxiety, it is better to prescribe selective serotonin reuptake inhibitors (e.g, citalopram, paroxetine).

These are usually well-tolerated but do not possess analgesic activity for neuropathic pain, in which case the serotonin and noradrenaline reuptake inhibitors (venlafaxine and, especially, duloxetine) are preferable.

There are no data on the use of other adjuvant analgesics (e.g., cannabinoids, topiramate and oxcarbazepine) in older patients. These can nevertheless be used, starting with low doses and titrating up progressively.

Phenytoin should not be used because of a narrow therapeutic index, frequent occurrence of adverse effects, several drug-drug interactions and limited analgesic activity. Carbamazepine should be kept for patients with trigeminal neuralgia or those not responding to other adjuvant analgesics, because it is also associated with toxicity.

Finally, topical analgesics (e.g., lidocaine, capsaicin) are always a good choice in older patients because they are devoid of systemic adverse effects.

Interventional approaches
Interventional approaches (e.g., epidural or intra-articular steroid injection, facet block) should always be considered in older patients. If successful, they can avoid prolonged daily use of analgesics.

Interdisciplinary treatment
Older patients are under-represented in interdisciplinary pain clinics because they are referred less often than younger patients. However, they respond just as well when the program is adapted to their specific needs. Because of their multiple comorbidities and functional impairments, they can even obtain better outcomes in terms of physical functioning, affective status and overall quality of life. Interdisciplinary programs with teams combining expertise in pain management and geriatric medicine, which have started to emerge, are often better equipped to address the complex and multifactorial needs of older patients.

Conclusion
Chronic pain is a frequent and detrimental problem in older patients, and is unfortunately often undertreated. However, when combining non-pharmacological, pharmacological and interventional approaches, ideally in an interdisciplinary setting, it is usually possible to provide pain relief that will preserve or improve the person’s functional autonomy and quality of life.

References and Suggested Readings

AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. Journal of the American Geriatrics Society, June 2002 (supplement).

Gibson SJ, Weiner DK, eds. Pain in older persons. Seattle: IASP Press, 2005.

Hadjistavropoulos T, Hadjistavropoulos H. Pain management for older adults: a self-help guide. Seattle: IASP Press, 2008.

Hadjistavropoulos T, Herr K, Turk DC, et al. An Interdisciplinary Expert Consensus Statement on Assessment of Pain in Older Persons. Clin J Pain 2007; 23:S1-43.

Lussier D, Pickering G. Pharmacological considerations in older persons. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH. Pharmacology of Pain. Seattle: IASP Press (in press).

Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol Med Sci 2003; 58A:76-81.

Morrison RS, Siu AL. A comparison of pain and its treatment in advanced dementia in cognitively intact patients with hip fracture. J Pain Sympt Manag 2000; 19:240-8.

Weiner DK, Herr K, Rudy TE, eds. Persistent pain in older adults: An interdisciplinary guide for treatment. New York, NY: Springer Publishing Company, 2002.