Analgesic Drug Classes
Opioids remain the gold standard for the treatment of moderate to severe acute pain. Morphine is a potent opiate analgesic that can be administered orally, intramuscularly, subcutaneously and intravenously. Morphine is easily titrated, provides a lasting analgesic effect and is inexpensive. Intravenous morphine can be safely used in cognitively intact older patients. Acutely, after surgery, the total dose of morphine, pain relief achieved and risk of adverse events is not significantly different than in younger patients.[46,47] Postoperatively, following transfer from the postanesthesia care unit, decreases in opioid requirements associated with advancing age have been demonstrated, whether received through intravenous patient-controlled analgesia (IVPCA) or by nursing administration.[47,48] It has also been demonstrated that cognitively intact older patients are quite capable of using an IVPCA, achieve similar reductions in pain and self-administer less overall opioid; however, they use the IVPCA for a longer duration compared with younger adults. A Cochrane review concluded that IVPCA provided superior analgesia and improved patient satisfaction compared with other conventional methods of delivery. Morphine is broken down in the liver to pharmacologically active metabolites (morphine-6-glucuronide and morphine-3-glucuronide), which are then excreted by the kidneys. In the setting of renal impairment, these metabolites can accumulate, causing respiratory depression and/or neuroexcitation. In the setting of renal impairment, opioids that do not have active metabolites, such as fentanyl, are preferred for IVPCA.
One potential problem with IVPCA is the practice of patient-controlled analgesia (PCA) by proxy (the administration of an IVPCA bolus dose by someone other than the patient). PCA by proxy has been associated with several fatalities in adult patients. This prompted a review by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), which recommended that no patient visitors be allowed access to the PCA device. The JCAHO also recommended PCA by nurse proxy be utilized only at those institutions where patient selection criteria and monitoring standards have been established. PCA by proxy is of particular concern in older patients who are not cognitively intact and cannot reliably use PCA.
Oral opioids are, of course, also widely used for acute pain management. Oral oxycodone undergoes less first-pass metabolism and has higher bioavailability than oral morphine. This results in more consistent plasma levels postadministration. Unlike morphine, renal impairment does not appear to affect plasma concentrations of oxycodone or its active metabolite oxymorphone. This is an important factor to consider, as renal impairment is a common comorbidity in the older population. The administration of scheduled controlled-release oxycodone may avoid the peaks and troughs associated with intravenous bolus dosing, resulting in stable plasma levels and improved pain control. A combination of long- and short-acting oxycodone was equally effective as IVPCA in patients undergoing total hip and total knee arthroplasty. Although the incidence of side effects was equal between groups, opioid consumption in the oxycodone group was significantly less than in the IVPCA group. Rothwell et al. showed oral oxycodone provided equivalent analgesia to IVPCA in a group of patients, aged 60–79 years, post-total hip arthroplasty. There is emerging evidence that oral oxycodone may be more cost effective than IVPCA in patients who have had laparoscopy surgery. Scheduled oral oxycodone (controlled release) improved patients' pain control, patient satisfaction, and decreased postoperative nausea and vomiting compared with intravenous morphine PCA in a group of patients post-lumbar discectomy. Oral oxycodone is also being administered with increased frequency as part of a multimodal approach to acute postoperative pain.[54,55,57] Oral and IVPCA approaches are just two of many ways to administer opioids. A discussion of the many differences in approach is, unfortunately, beyond the scope of this article.
Common opioid side effects reported in the literature include urinary retention, pruritus, nausea and vomiting, CNS effects and respiratory effects. The incidence of each adverse drug effect varies by the specific opioid given and the route of administration.
By far the most feared opioid-induced toxicity is respiratory depression. Respiratory depressive side effects comprise the majority of severe opioid adverse effects. Adverse outcomes from respiratory depression can typically be prevented through opioid titration and vigilant monitoring. When necessary, naloxone (an opioid antagonist) can be administered. Naloxone can cause opioid withdrawal, sudden severe pain, hypertension and pulmonary edema. The manufacturer of naloxone recommends administering this medication in the lowest effective dose to geriatric patients as it has not been thoroughly studied in this population, although clinical experience suggests there is no difference between older and younger patients.
Opioid tolerance is an increasingly prevalent challenge in perioperative care. Approximately 15 years ago, the concept of 'pain as the fifth vital sign' was popularized in the USA, and aggressive pain treatment was mandated by hospital credentialing organizations such as JCAHO. Unfortunately, this involved the use of high doses of opioids for chronic (and often ill-defined) conditions, despite minimal evidence that opioids are effective as long-term analgesics.
With chronic use of opioids, opioid receptors decrease in population, as well as possibly in excitability. This 'downregulation' of opioid receptors manifests as increasing doses of opioids needed to obtain the same effect, and is usually clinically noted as 'tolerance' to a drug. Unfortunately, in up to 30–40% of patients that chronically consume opioids, opioid-induced hyperalgesia occurs. This condition refers to a generalized and increasing pain sensitivity that occurs with chronic opioid use. Patients note that many areas of their body hurt, rather than just the region that they originally sought treatment for. Minor medical procedures, such as immunizations, venopunctures or intravenous catheter insertions, are perceived as excruciating. Higher doses of opioids are often prescribed by well-intentioned clinicians, but are not helpful, and frequently cause a further pain sensitivity.
The precise mechanism of action of paracetamol remains poorly understood. Its antinociceptive (pain-relieving) activity is generally thought to be due to central prostaglandin; inhibition however, central COX-2 inhibition and descending serotonergic modulation may also contribute to its analgesic properties. Unlike NSAIDs, it has minimal peripheral COX enzyme inhibition, which in turn limits its side effects. In patients with severe liver disease elimination half-life can be prolonged and a reduction in dose and duration is recommended. Most prescribers avoid paracetamol administration in alcohol abusers due to fears of hepatotoxicity. Coadministration of paracetamol and alcohol is known to produce the hepatotoxic metabolite N-acetyl-p-benzoquinoneimine. Interestingly, a prospective study administering therapeutic doses of paracetamol to patients enrolled in an alcohol detoxification center found no evidence of liver injury.
Paracetamol's opiate-sparing properties are well established in the postoperative setting. Paracetamol reduces opioid consumption compared with placebo in a variety of postoperative settings including total hip replacement, total knee replacement, hysterectomy and tonsillectomy.[64–66] Despite consistent reduction in 24 h postoperative morphine consumption, no apparent reduction has been found in opioid-related side effects after major surgery.[67,68]
Route of administration with paracetamol is a consideration. Given orally it does not undergo significant first-pass metabolism in the liver and its oral bioavailability is estimated between 63–89%. Rectal administration is much less reliable as absorption is slower and much less predictable, with bioavailability between 24–98%. Factors affecting rectal absorption include the number of suppositories used, the size of the suppositories and a patient's rectal pH. Half-life and clearance of oral acetaminophen is not significantly different in the older population. A dose regimen of 1 g three-times daily is safe without evidence of drug accumulation.
Intravenous acetaminophen is appropriate when oral or rectal acetaminophen administration is not appropriate. Intravenous administration results in more rapid pain relief and treatment of fever compared with enteral routes. Dosage and side effects are similar with all routes of administration.
NSAIDs are amongst the most commonly used medications for the treatment of acute pain. In 2000, 70% of adults over age 65 years were taking NSAIDs at least once a week. These drugs exert their analgesic and anti-inflammatory effects by diminishing peripheral and/or central prostaglandin production through the inhibition of the COX enzyme. The COX enzyme exists in two forms: COX-1 and -2. These enzymes are reversibly inactivated by nonselective NSAIDs. Ketorolac, diclofenac, ibuprofen, naproxen and ketoprofen are nonselective NSAIDs that enhance pain relief, induce opioid-sparing effects, and may reduce opiate adverse effects such as urinary retention, nausea and vomiting.[74,75] A recent meta-analysis by Maund et al. confirmed the opioid-sparing properties of NSAIDs; however, a decreased incidence in nausea and vomiting was the only adverse opioid side effect significantly reduced.
Elderly patients are at increased risk of complications from NSAIDs, including renal injury, gastrointestinal bleeding, platelet inhibition, hypertension and congestive heart failure. Advanced age is a primary risk factor for adverse gastrointestinal events associated with NSAID administration. The mortality rate among patients hospitalized for NSAID-induced upper gastrointestinal bleeding is approximately 5–10%. It has been estimated that approximately 16,500 NSAID-related deaths occur each year. Unfortunately only a minority of patients experiencing serious gastrointestinal complications report any antecedent dyspepsia.[76,77] The pathogenesis of gastroduodenal mucosal injury is thought to be due to the inhibition of endogenous prostaglandin synthesis. Prostaglandin inhibition leads to a reduction in the production of protective epithelial mucous and bicarbonate rendering the mucosa vulnerable to injury. COX-1 is found in most tissues throughout the body including gastric mucosa, kidneys and platelets. Conversely, COX-2 is thought to be inducible, predominantly expressed only in damaged tissue at the time of injury.
Celecoxib is a selective COX-2 inhibitor, meaning that it only inhibits the COX-2 enzyme and not the COX-1 enzyme. This selectivity drastically reduces the incidence of gastroduodenal ulceration. However, COX-2 inhibitors are not free of renal complications, particularly in patients with dehydration, pre-existing renal insufficiency or with concomitant administration of other nephrotoxic drugs. Celecoxib is the only COX-2 inhibitor which remains commercially available in the USA, as rofecoxib and valdecoxib were withdrawn from the US market due to concerns of adverse cardiovascular events.[80,81] Celecoxib is usually not used in patients at risk for thromboembolic complications, such as stroke or heart attacks. Long-term use of celecoxib carries a dose-related risk of adverse events, including death from cardiovascular causes, myocardial infarction, stroke and heart failure. Knowledge of the chronic use of these medications is important as they may contribute to comorbidities that must be known prior to instituting other types of therapy.
An additional concern associated with NSAIDs is that the very anti-inflammatory effects that make them effective analgesics may adversely affect healing processes that require inflammation. One such area is bone healing, including fractures and effectiveness of bone fusions in spine surgery. NSAID administration has been shown to inhibit osteogenic activity and fracture healing in animal models.[84,85] Additional animal data suggests that NSAID administration adversely affects fusion rates post spinal surgery.[86,87] Glassman et al. performed a retrospective analysis and found that ketorolac significantly inhibited spinal fusion in adults and recommended that it be avoided in the postoperative period. This is often cited by our surgical colleagues as a reason to omit NSAIDs in the postoperative period. However, these findings were not reproducible and were recently refuted in both the adult and pediatric populations.[89,90] The studies showing ketorolac to be safe in the postoperative period limited its administration to the first 48 h. In addition, piroxicam has not been found to significantly alter bone healing following Colles' fracture in postmenopausal women.
Gabapentin and its successor pregabalin are anticonvulsants that decrease perioperative pain and limit long-term wound hypersensitivity.[92,93] This latter property is particularly important with those surgeries that have high rates of chronic wound pain: mastectomy, hysterectomy, inguinal hernia repair and thoracotomy. All of these types of surgery involve cutting peripheral nerves and inducing wound hypersensitivity.
The gabapentinoids (gabapentin and pregabalin) bind presynaptic voltage-gated calcium channels located in the dorsal root ganglion and spinal cord, resulting in the inhibition of excitatory neurotransmitter release. Gabapentin has a well-established role in the treatment of chronic and neuropathic pain[95–97] related to its ability to prevent spinal cord pain sensitization following noxious surgical or traumatic tissue injury. Preoperative administration of gabapentin has been shown to have opioid-sparing effects (approximately a 40% decrease) in both adult and pediatric surgical populations.[99–101] Gabapentin also reduces opiate-related side effects such as nausea, vomiting and urinary retention.
Adverse effects associated with perioperative administration of the gabapentinoids are infrequent. An increased incidence of sedation and a trend towards more patient dizziness may limit their use in the ambulatory surgical setting. Gabapentinoids are not metabolized prior to renal elimination; therefore, dose adjustments are required for patients with renal insufficiency. One of the disadvantages of gabapentin is its saturable absorption (only a certain amount of drug can be absorbed in the GI tract per unit of time), which leads to frequent dosing and large amounts of drug that are not absorbed. Newer gabapentinoids, such as pregabalin, are well absorbed after oral administration and do not have saturable absorption. Whether or not this makes pregabalin the anticonvulsant of choice for the treatment of acute pain in the elderly will depend on further experience.
N-methyl-D-aspartate Receptor Antagonists
The N-methyl-D-aspartate (NMDA) receptor is primarily found in the dorsal horn of the spinal cord and brain, and modulates prolonged pain states. After tissue injury, the NMDA receptor is involved in the sensitization of the spinal cord as well as diminished responsiveness to opioid analgesics. Ketamine is an NMDA receptor antagonist, which has shown promise in the treatment of chronic pain syndromes in opioid-tolerant patients.[105,106] Given that intraoperative and postoperative noxious stimuli may also cause central sensitization, recent studies have focused on NMDA receptor antagonism in the treatment of acute pain. According to a recent review, perioperative administration of ketamine reduced pain and analgesic consumption in the postoperative period.[107,108] Subanesthetic ketamine dosing was found to lower pain scores, reduce morphine consumption and shorten postoperative IVPCA dependence in orthopedic patients with malignancy. These results were reproduced in a cancer-free patient population undergoing total hip arthroplasty. In addition to a reduction in morphine consumption the authors noted improved rehabilitation at day 30 and a reduction in pain at rest up to 6 months after the procedure.
NMDA receptors also play a role in the mediation of visceral pain and peripheral nerve pain sensitization. Ketamine has been found to enhance analgesic and anesthetic effects of local anesthetic infiltration suggesting a peripheral mechanism in addition to its central effects. Ketamine infiltration prior to injury has also been found to decrease the development of secondary hyperalgesia (an increased sensitivity to a painful stimulus in the area surrounding damaged tissue).
A major limitation of the NMDA receptor antagonists is their side effects. Glutamate agonism at brain NMDA receptors is involved in thought formation, learning and memory. NMDA receptor stimulation appears to be involved in both normal neuronal function and upregulated in pathologic pain states. Not surprisingly, antagonism at NMDA receptors may result in the undesirable side effects of sedation, disorientation, hallucinations and flashbacks. Clinician concern over ketamine's side effect profile has limited its use, however, low-dose ketamine can be safely used. Memantine is a long-acting oral NMDA receptor antagonist with few side effects at therapeutic concentrations. Its effectiveness in the treatment of acute pain remains unproven although second generation derivatives are currently being tested.
Aging Health. 2011;7(6):813-828. © 2011 Future Medicine Ltd.