Individualizing the Selection of Nonopioid Analgesics

Chapter 7


Individualizing the Selection of Nonopioid Analgesics



THE POTENTIAL risks and benefits of nonopioid analgesic therapy should be considered in developing a plan of care for all patients with pain. Most clinicians will consider trying a nonopioid unless there is clear evidence of nonefficacy or increased risk. Once the decision is made to try one of these drugs, the goal is to select an agent and a dose that offers satisfactory pain relief with a low risk of adverse effects. Decisions about drug and dose may be influenced by the patient’s past experience, pain syndrome, and the assessed risk factors for adverse effects. The patient’s ability to pay for nonopioid therapy also should be evaluated. Table 7-1 is a guide to generic and brand names of nonopioids and may be used in conjunction with Table 7-2, which details dosing information and other characteristics for acetaminophen and NSAIDs. See Chapter 6 regarding individualizing the selection of nonopioid analgesics based on GI risk and cardiovascular (CV) risk. See patient medication information in Forms III-1 through III-5 on pp. 250-259.



Guidelines



Table 7-2


Acetaminophen and NSAIDs: Adult Dosing Information


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CV, Cardiovascular; GI, gastrointestinal; h, hour; IM, intramuscular; IV, intravenous; mg, milligram; PO, oral; q, every


Clinical Relevance of Information Presented in Table 7-2:


Half-life. Half-life is the time required for 50% of the dose to be eliminated from the body. A short half-life (approximately 2 to 7 hours) is recommended for some patients, such as older adults. Drugs with a short half-life are usually preferred for occasional or unexpected pain because they tend to have a quicker onset of analgesia than drugs with a long half-life.


Dosing schedule. Dosing intervals may range from every 4 hours to once a day. Drugs with short half-lives have shorter dosing intervals than those with long half-lives. If patients can tolerate a drug with a long half-life, dosing once or twice a day is usually preferred. The fewer the doses, the more likely the patient will remember to take the drug.


Recommended starting dose. This dose should be reduced by one half to two thirds in older adults, those taking multiple drugs, or those with renal insufficiency.


Maximum dose recommended. Data are lacking, but the dose listed is thought to be the maximum needed by most patients for analgesia and the dose beyond which adverse effects are more likely. However, in some patients careful dose titration may identify patients who need and tolerate 50% to 100% more than the maximum dose recommended. Others may require or tolerate less. For some patients at risk for adverse effects, the maximum daily dose may be one half or less than recommended.


1All of the drugs in Table 7.2 are oral formulations and all doses are oral doses unless specified otherwise.


2Avoid full doses in older adults due to long half-life and increased risk of GI toxicity.


From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, pp. 211-213, St. Louis, Mosby. Data based on the clinical experience of the authors and a variety of published sources, including: American Geriatrics Society (AGS) Panel on Pharmacological Management of Persistent Pain in the Older Persons. (2009). The pharmacological management of persistent pain in older persons. J Am Geriatr Soc, in press; American Pain Society (APS). (2003). Principles of analgesic use in the treatment of acute pain and cancer pain, ed 5, Glenview, IL, APS; Burke, A., Smyth, E., FitzGerald, G. A. (2006). Analgesic-anti-pyretic agents: Pharmacotherapy of gout. In L. L. Brunton, J. S. Lazo, & K. L. (Eds.), Goodman, Gilman’s the pharmacological basis of therapeutics, ed 11, New York, McGraw-Hill; Drug facts and comparisons. (2006). St. Louis, Wolters Kluwer Health; Fick, D. M., Cooper, J. W., Wade, W. E., et al. (2003); Updating the Beers criteria for potentially inappropriate medication use in older adults. Arch Intern Med 163(22):2716-2724; Gold Standard, Inc. Available at http://clinicalpharmacology.com. Accessed August 20, 2008; Hanlon, J. T., Backonja, M., Weiner, D., et al. (2009). Evolving pharmacological management of persistent pain in older persons. Pain Med, 10(6), 959-961; Motov, S. M., & Ast, T. D. (2008). Is there a limit to the analgesic effect of pain medications? Medscape Emergency Medicine. Available at http://www.medscape.com/viewarticle/574279. Accessed July 18, 2008; Simon, L. S., Lipman, A. G., Caudill-Slosberg, M., et al. (2002). Guideline for the management of pain in osteoarthritis, rheumatoid arthritis, and juvenile chronic arthritis. Glenview, IL, American Pain Society; Smith, H. S., & Baird, W. (2003). Meloxicam and selective COX-2 inhibitors in the management of pain in the palliative care population. Am J Hosp Palliat Care, 20(4), 297-306; Vardeny, O., & Solomon, S. D. (2008). Cyclooxygenase-2-inhibitors, nonsteroidal anti-inflammatory drugs, and cardiovascular risk. Cardiol Clin, 26(4), 589-601. Pasero C, McCaffery M. May be duplicated for use in clinical practice.





General Considerations





Pain Intensity


Several Cochrane Collaboration Reviews underscore the importance of evaluating the patient’s pain intensity when determining the appropriate nonopioid to administer. As mentioned earlier, acetaminophen has been shown to produce better pain relief than placebo, but NSAIDs were superior for osteoarthritis (OA) pain (Towheed, Maxwell, Judd, et al., 2006) (see pp. 220-221 for more on OA). Another Cochrane Collaboration review evaluating 51 studies and 5762 patients with moderate to severe postoperative pain concluded that acetaminophen provided effective analgesia for just half of the patients for 4 to 6 hours (Toms, McQuay, Derry, et al., 2008). These reviews support the appropriateness of acetaminophen as a first-line choice for mild pain and NSAIDs alone or in combination with other analgesics, including acetaminophen, for more severe pain.



Current Analgesic Response


Patients vary in response to nonopioids. If one nonopioid is ineffective after appropriate dose adjustment, it is worthwhile to try another. There is very little evidence to guide these so-called sequential trials, and assessment of risk and benefit should precede each decision about a new drug and dose.


A nonopioid should not be considered ineffective until the dose-response relationship has been explored and the clinician is certain that the dose has been increased either to (1) the highest dose conventionally accepted with the drug in question, (2) the dose associated with adverse effects, or (3) the dose that confirms that no additional analgesia is occurring with increases (i.e., a dose above the ceiling dose for analgesia). Many clinicians believe that it takes a few days to a week to evaluate the analgesia produced at a specific dose of an NSAID (Burke, Smyth, Fitzgerald, 2006), and a trial of at least 2 to 3 gm of acetaminophen per day for several weeks is recommended to evaluate the effectiveness of this drug (Simon, Lipman, Caudill-Slosberg, et al., 2002). Obviously, if severe adverse effects occur, the nonopioid should be stopped and another tried or the appropriateness of nonopioid therapy reconsidered.



Frequency of Dosing


Acetaminophen and NSAIDs may be given PRN for occasional pain or around the clock (ATC) for ongoing pain. Acetaminophen has a short half-life and usually must be given every 4 hours for ongoing pain. The half-lives of NSAIDs differ, and dosing intervals range from every 4 hours to once a day (see Table 7-2). For persistent pain, the use of once or twice a day dosing usually is more convenient and more likely to result in the patient taking all prescribed doses, which will lead to better pain control. This requires an NSAID with a long half-life or one that is formulated for modified release. However, it is recommended that full doses of naproxen, piroxicam, and oxaprozin be avoided in older adults because of their long half-life and an increased risk of GI toxicity (Fick, Cooper, Wade, et al., 2003; Hanlon, Backonja, Weiner, et al., 2009) (see Chapter 6 and later discussion about half-life in this chapter). When patients are taking other analgesics or medications, consideration should be given to NSAIDs that allow for scheduling as many doses as possible at the same time.


Research has shown that once-daily dosing of celecoxib may be safer from a CV perspective than twice-daily dosing, even of the same total daily dose (Vardeny, Solomon, 2008). The maximum plasma concentration of celecoxib is reached in 90 minutes after intake, and the drug has a short half-life of just 1.5 hours (Paulson, Hribar, Liu, et al., 2000). The COX-2 effect of celecoxib (and other NSAIDs) inhibits prostacyclin, a vasodilator that antagonizes platelet aggregation, and prostacyclin levels require approximately 12 hours to recover following a single oral dose of celecoxib (McAdam, Catella-Lawson, Mardini, et al., 1999). Once-daily dosing may allow enough prostacyclin recovery and normalization to attenuate any thrombotic effect (Grosser, Fries, FitzGerald, 2006; Vardeny, Solomon, 2008). Although further research is needed, the findings in other studies that utilized once-daily dosing support this theory (Sowers, White, Pitt, et al., 2005; Whelton, Fort, Puma, et al., 2001). See Chapter 6 for an extensive discussion of this and the other CV effects of NSAIDs.



Routes of Administration


NSAIDs are taken most often by the oral route of administration. All NSAIDs are available orally, and a few are available parenterally, rectally, and topically. Currently in the United States the only NSAIDs available for parenteral administration are ketorolac (Toradol), ibuprofen (Caldolor), and indomethacin (Indocin). Ketorolac is widely used parenterally as an analgesic for short-term pain (e.g., postoperative), and IV ibuprofen is approved for treatment of acute pain and fever; parental indomethacin is used primarily in infants for closure of patent ductus arteriosus (Burke, Smyth, Fitzgerald, 2006). Other countries have many nonopioids available parenterally, including acetaminophen, aspirin, ketoprofen, parecoxib, and diclofenac. At the time of publication, IV acetaminophen (Acetavance) (http://www.cadencepharm.com/products/apap.html) and injectable diclofenac (Dyloject) were in development for approval in the United States (Colucci, Wright, Mermelstein, et al., 2009). An intranasal formulation of ketorolac in a disposable, metered spray device for ambulatory patients with acute pain was also in development in the United States (Brown, Moodie, Bisley, et al., 2009; Moodie, Brown, Bisley, et al., 2008). See Chapter 8 for more on these nonopioid formulations.



Rectal Nonopioid Administration


Rectal NSAIDs are used far more often in countries other than the United States. Relatively few are available commercially for rectal administration in the United States, but most pharmacies can compound them as rectal suppositories. Oral formulations can also be administered rectally, either by using the intact tablet or by placing the intact or crushed tablet in a gelatin capsule and inserting the capsule into the rectum (Pasero, McCaffery, 1999). (Note that modified-release nonopioids should not be crushed.) Because rectal NSAIDs have an 80% to 90% oral bioavailability, higher rectal than oral doses may be required to achieve similar effects (Beck, Schenk, Hagemann, et al., 2000). (See Chapter 8 for discussion of rectal administration of perioperative nonopioids and Chapter 14 for rectal administration technique.)



Topical NSAIDs


Of all of the drugs administered topically, the largest amount of clinical evidence exists for NSAIDs (Stanos, 2007). They are used and researched more extensively in Europe than in the United States. The NSAIDs that are administered topically most often are diclofenac, ibuprofen, ketoprofen, piroxicam, and naproxen, but not all are available commercially in topical formulation in the United States (Moore, Derry, McQuay, 2008). Diclofenac is available in both gel and patch formulations. Other topical NSAIDs, such as ketoprofen and naproxen, are in development and are likely to become commercially available in the United States (McCleane, 2008). Compounding pharmacies sometimes prepare topical mixtures that contain NSAIDs when they are not available commercially (Coyne, Hansen, Watson, 2003).


Although cyclooxygenase (COX) inhibition is a primary mediator of NSAID analgesia by any route of administration, research is ongoing to elucidate all of the underlying mechanisms of action of topical NSAIDs. For example, in addition to COX inhibition, animal research has demonstrated that topical diclofenac inhibits peripheral NMDA (N-methyl-d-aspartate) receptors (Dong, Svensson, Cairns, 2009), and high tissue concentrations of diclofenac are capable of blocking sodium channels to mediate local anesthetic-like effects (Cairns, Mann, Mok, et al., 2008) (see Section I for more on the role of sodium channels and NMDA receptor antagonism in analgesia). The therapeutic effect of topical NSAIDs is the result of high concentrations of drug in the tissue rather than the systemic circulation (Galer, Rowbotham, Perander, et al., 2000; Mazieres, 2005; Sawynok, 2003; Stanos, 2007). The best use of topical NSAIDs, therefore, is for well-localized pain, such as arthritic joint or soft-tissue injury pain (Galer, Rowbotham, Perander, et al., 2000; McCleane, 2008). The effectiveness of a topical NSAID depends on its ability to reach the tissue generating nociception (Moore, Derry, McQuay, 2008). (See Chapter 24 for discussion of topical vs. transdermal drug delivery and Figure 24-1 on p. 685)


The bioavailability of an NSAID after topical application is 5% to 10% compared with equivalent oral administration (Heyneman, Lawless-Liday, Wall, 2000; Mazieres, 2005). For comparison, oral NSAIDs have a 50% to 70% oral bioavailability after first-pass effect (Wilbeck, Schorn, Daley, 2008). Thus, compared with other routes of administration, topical NSAIDs provide the benefits of a low incidence of systemic adverse effects and the potential for fewer drug-drug interactions (Bannwarth, 2006; Galer, Rowbotham, Perander, et al., 2000; Heyneman, Lawless-Liday, Wall, 2000; McCleane, 2008; Rainsford, Kean, Ehrlich, 2008).


Given their low systemic distribution, topical NSAIDs may be particularly advantageous in patients who have well-localized painful conditions that may respond to NSAID therapy but are at high risk for NSAID adverse effects, such as older adults with OA (McCleane, 2008) (see pp. 220-221 for more on OA). Patients should be advised that they may take acetaminophen concurrently but should avoid other NSAIDs while taking topical NSAIDs because this can increase the incidence of adverse effects (Galer, Rowbotham, Perander, et al., 2000; McCleane, 2008).


Although topical NSAIDs have a lower risk of adverse effects than systemically-administered NSAIDs, it is important to understand that some drug is absorbed and the risk of serious toxicity is not nil. GI adverse effects from a topical NSAID are more likely in individuals who have experienced a previous GI adverse effect, in a manner similar to orally-administered drugs (McCleane, 2008; Sawynok, 2003). Therefore, tolerability should be regularly assessed during topical NSAID use, particularly in patients with a history of GI adverse effects. Postmarketing surveillance identified reports of hepatotoxicity during the first months of treatment with diclofenac gel (Voltaren), prompting the revision of prescribing information for the drug to state that liver enzyme testing should be done within the first 4 to 8 weeks of treatment initiation (Dawson, 2010).


Topical NSAIDs are used for both acute and persistent (chronic) pain, but their effectiveness has been questioned over the years (McCleane, 2008; Moore, Derry, McQuay, 2008; Simon, 2008). A systematic review of the use of rubefacients (counterirritants) containing salicylates concluded that there is a lack of well-designed and controlled research regarding their use and adverse effects and reported poor efficacy for persistent pain and limited evidence of efficacy for acute pain treatment (Mason, Moore, Edwards, et al., 2004b). One major drawback is that many of the currently available or compounded topical NSAIDs are in short-acting gel or cream formulations only, which have a relatively brief duration of action (McCleane, 2008). This limits their usefulness, particularly for persistent pain. Gels and creams can also be messy and result in inexact dosing and disruption if the preparation is rubbed off. Gels are reported to be more effective than creams (Moore, Derry, McQuay, 2008).


Topical patch formulations seem to be a better option because they allow uniform application, which results in more controlled delivery than is possible with gels or creams (Rainsford, Kean, Ehrlich, 2008; Stanos, 2007). Steady state maximum plasma concentration of the diclofenac epolamine 1.3% patch (Flector) is reached in 5.4 hours following application of the patch, and it has a half-life of 26.4 hours. Significant accumulation of topical diclofenac occurs in the synovial fluid and musculature (Moore, Derry, McQuay, 2008). There are no clinically relevant metabolites, and mild GI symptoms and dermal reactions occur in 2% and 10% of patients, respectively (Rainsford, Kean, Ehrlich, 2008). Patches must be changed every 12 hours for continuous relief.


Patients often like the idea of applying medication directly to a painful area (Underwood, Ashby, Cross, et al., 2008); however, not all pain is responsive to topical NSAIDs; if pain relief is not apparent within a few hours, sustained use is not justified and alternative methods of pain control should be implemented (McCleane, 2008). As with all NSAIDs, the lowest effective dose for the shortest time necessary should be used.



Topical NSAIDs for Acute Pain: A systematic review of 26 double-blind, placebo-controlled trials analyzed data from 2853 patients to evaluate the efficacy and safety of a variety of topical NSAIDs for acute pain conditions, such as sprains and strains (Mason, Moore, Edwards, et al., 2004c). Compared with oral NSAIDs, topical NSAIDs provided better pain relief and similar adverse effects and treatment success. Withdrawals due to an adverse event were rare. Ketoprofen was more effective than topical ibuprofen, piroxicam, and indomethacin; there was no comparison data on diclofenac.


Zacher and colleagues (2008) performed a review of 19 double-blind, randomized, placebo- or active-controlled trials (> 3000 patients) of topical diclofenac. They concluded that this formulation is effective in reducing pain and inflammation associated with acute soft-tissue injury; benefits included functional improvement, a low incidence of mild dermal adverse effects, and fewer adverse effects than other topical and oral NSAIDs. Banning (2008) found that topical diclofenac in a variety of formulations was either superior or equivalent to oral diclofenac or placebo for orthopedic soft-tissue injury pain. Topical diclofenac produced significant reductions in pain and morning stiffness, and improved physical function. Again, minor dermatitis-type adverse effects were reported. Randomized, placebo-controlled trials that have focused specifically on the diclofenac 1.3% patch formulation have reported similar positive results for sports-related soft-tissue injuries (Galer, Rowbotham, Perander, et al., 2000; Predel, Koll, Pabst, et al., 2004).


At the time of publication, a topical patch containing 100 mg of ketoprofen was in development in the United States. Phase III trials in patients with traumatic soft-tissue injuries and other musculoskeletal pains have shown the patch to be more effective than placebo and similar to the diclofenac patch, to produce minor dermal adverse reactions, and to be associated with a low incidence of GI adverse effects (Mazieres, 2005). For example, a randomized, double-blind, 14-day study of 172 patients showed that the ketoprofen patch was safe and effective in relieving tendonitis (Mazieres, Rouanet, Guillon, et al., 2005). Other research has suggested that the ketoprofen patch may yield slightly better pain relief during activity and higher patient satisfaction than the diclofenac gel (Esparza, Cobian, Jimenez, et al., 2007).


Ibuprofen cream also has been used as a topical analgesic for acute pain. One study found no significant differences in pain relief at rest and with movement between oral ibuprofen 400 mg and ibuprofen 5% gel, both administered 3 times daily, for acute soft-tissue injuries (Whitefield, O’Kane, Anderson, 2002). A placebo-controlled study found that application of 5% ibuprofen cream 2 hours before elective external direct current cardioversion safely and effectively reduced pain and inflammation (Ambler, Zidema, Deakin, 2005); the researchers concluded that it should be used routinely prior to this procedure.


A foam dressing permeated with ibuprofen (Biatain Ibu) is used outside of the United States for the care of painful wounds. One randomized, controlled study showed that the use of ibuprofen foam dressings reduced pain and improved quality of life with minimal adverse effects in patients with painful exuding wounds (Palao, Domenech, Romanelli, et al., 2008). Another study found similar results with the combined use of the ibuprofen-releasing foam dressing and silver-releasing contact layer on locally infected, exuding venous leg ulcers (Jorgensen, Gottrup, Karlsmark, et al., 2008). Pain during dressing change was reduced, and persistent pain decreased from 6.2 to 3.0 (0 to 10 scale) with minimal adverse effects.



Topical NSAIDs for Persistent (Chronic) Pain: Numerous high-quality studies have shown the superiority of topical NSAIDs compared with placebo for persistent pain (McCleane, 2008; Moore, Derry, McQuay, 2008). An extensive, systematic literature review that included 14 randomized, double-blind trials with data on over 1500 patients comparing topical NSAIDs with either placebo or other active treatment concluded that topical NSAIDs were safe and effective for persistent musculoskeletal pain (Mason, Moore, Edwards, et al., 2004c). Local and systemic effects were minimal and similar to placebo.


Topical NSAIDs are presented as first-line analgesic options in a variety of clinical guidelines (Hunter, Lo, 2008). The United Kingdom’s National Collaborating Centre for Chronic Conditions recommends that topical NSAIDs be the core treatment for knee and hand OA and, with acetaminophen, should be tried before oral NSAIDs (NCC-CC, 2008). Others have supported this recommendation (Moore, Derry, McQuay, 2008). However, an extensive literature review on the use of topical NSAIDs for the treatment of OA pain concluded that topical NSAIDs produced better pain relief than placebo but inferior pain relief compared with oral NSAIDs (Lin, Zhang, Jones, et al., 2004). A controversial finding of this study was that the pain relief from topical NSAIDs did not extend beyond 2 weeks. This review has been criticized for many reasons, primarily design flaws, and the finding that topical NSAIDs work for only 2 weeks has not been supported by other research (Moore, Derry, McQuay, 2008).


Topical diclofenac has been extensively evaluated in placebo-controlled trials of longer duration. A 4-week randomized, placebo-controlled trial (N = 248) evaluating the effect of topical 1.5% diclofenac solution on OA knee pain found that patients taking diclofenac experienced significantly less pain on walking and improved physical function, and that patient global assessments were superior (Bookman, Williams, Shainhouse, 2004). Adverse effects, such as localized dry skin, were minor. Active drug and placebo groups had similar rates of GI and renal adverse events, suggesting that the topical drug had minimal systemic absorption. A randomized placebo-controlled 8-week trial (N = 385) of 1% diclofenac gel use for hand osteoarthritis (OA) demonstrated significant improvements in pain and global rating of disease; treatment was well tolerated with mild adverse effects, such as application-site paresthesia (Altman, Dreiser, Fisher, et al., 2009). Placebo-controlled studies of 6-week (Baer, Thomas, Shainhouse, 2005) and 12-week (Roth, Shainhouse, 2004) durations evaluated 1.5% diclofenac solution in 216 and 326 patients with knee OA, respectively, and found similarly positive results on pain, function, and patient satisfaction, with no systemic adverse effects. A randomized, placebo-controlled study (N = 153) established that the diclofenac (60 mg) patch produced effective pain control, improved function, and minimal adverse effects for myofascial pain syndrome (Hsieh, Hong, Chern, et al., 2010).


Similar findings were obtained when topical diclofenac was compared with other NSAIDs. The previously mentioned review by Zacher and colleagues (2008) of 19 double-blind, randomized trials (more than 3000 patients) concluded that topical diclofenac produced outcomes in OA pain that were better than other topical NSAIDs and oral diclofenac, ibuprofen, or naproxen. Topical diclofenac has also been shown to be as effective as oral diclofenac in reducing morning stiffness (Banning, 2008). In contrast, another systematic review found no significant differences in effectiveness or systemic effects between topical diclofenac and oral diclofenac, ibuprofen, and indomethacin (Moore, Derry, McQuay, 2008), and a study of a gel formulation of topical 1.16% diclofenac produced comparable findings (Niethard, Gold, Solomon, et al., 2005). More head-to-head research is needed to better compare the effectiveness of topical and oral NSAIDs.


Longer trials of other topical NSAIDs are very limited, and there are no clear conclusions. A randomized, controlled study found that 200 mg of ibuprofen cream (5%) applied to the knee in a 10-cm strip 3 times daily for 1 week provided better pain relief at rest, and overall, than placebo in patients with knee OA (Trnavsky, Fischer, Vogtle-Junkert, et al., 2004). This study confirmed earlier placebo-controlled research on ibuprofen cream (Rovensky, Micekova, Gubzova, et al., 2001). An interesting randomized 1-year study required researchers to advise patients with knee OA to use either oral or topical ibuprofen depending on the patient’s preferred route of administration (Underwood, Ashby, Cross, et al., 2008); although patients preferred topical ibuprofen, and both oral and topical ibuprofen were safe, neither were particularly effective, presumably because of relatively poor adherence. The latter study suggests that the outcomes of controlled trials with high adherence may overestimate the benefits actually obtained in clinical practice.


Piroxicam 0.5% gel was found to produce similar effectiveness and tolerability when compared with a gel containing a variety of homeopathic ingredients (van Haselen, Fisher, 2000). The authors recommended concomitant PRN administration of other “simple” analgesics but offered no specific suggestions. Piroxicam is noted to be theoretically inferior in terms of penetration compared with other more commonly used NSAIDs, such as ibuprofen and ketoprofen (Moore, Derry, McQuay, 2008).

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Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Individualizing the Selection of Nonopioid Analgesics

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