Multipurpose Adjuvant Analgesics

Chapter 22


Multipurpose Adjuvant Analgesics



DATA supporting the analgesic efficacy of some adjuvant drug classes are derived from numerous studies of very diverse syndromes. These drugs may be termed multipurpose and can be considered for any type of pain, fundamentally similar in this way to the opioids and nonopioid analgesics (Portenoy, 2000). The multipurpose adjuvant analgesics that are currently considered to be among the more useful in clinical practice include antidepressants, corticosteroids, and alpha2-adrenergic agonists (e.g., clonidine). Many of the multipurpose adjuvant analgesics are appropriate for both acute pain and persistent pain. Antidepressants have a delayed onset of analgesia, making them inappropriate for acute pain. Other drug classes, such as the sodium channel blockers and cannabinoids, have evidence to suggest broad applicability, but conventional use continues to position them solely for neuropathic pain (Lussier, Portenoy, 2004). Although the use of topical drugs is restricted by the location of pain, there are many types, and, combined, they too may be considered to have multiple purposes (see Chapter 24). See Table V-1, pp. 748-756, at the end of Section V for the characteristics and dosing guidelines for many of the multipurpose adjuvant analgesics.



Antidepressant Drugs


Antidepressant adjuvant analgesics are usually divided into two major groups: the tricyclic antidepressants (TCAs) and the newer biogenic amine reuptake inhibitors (Table 22-1). Of the latter group, the serotonin and norepinephrine reuptake inhibitors (SNRIs) are clearly analgesics, whereas research is lacking or inconsistent regarding the analgesic potential of the selective serotonin reuptake inhibitors (SSRIs) (Arnold, 2007; Collins, Moore, McQuay, et al., 2000; Kroenke, Krebs, Bair, 2009; Saarto, Wiffen, 2007; Veves, Backonja, Malik, 2008).



The multipurpose nature of antidepressants is demonstrated in their efficacy as analgesics in neuropathic pain states, such as painful diabetic neuropathy and postherpetic neuralgia, and other types of persistent pain states, such as headache, fibromyalgia, and some types of back pain. A meta-analysis of 18 randomized controlled trials concluded that there is strong evidence for the use of antidepressants in the treatment of fibromyalgia, with impressive improvements in pain, depression, fatigue, sleep disturbances, and health-related quality of life (Hauser, Bernardy, Uceyler, et al., 2009). These data have influenced treatment guidelines for fibromyalgia, which now include the early use of antidepressants (Hauser, Thieme, Turk, 2009). Guidelines also suggest that antidepressants should be considered an option for persistent low back pain, notwithstanding the lack of research focused on the newer drugs, specifically the SNRIs (Chou, Qaseem, Snow, et al., 2007).


An early systematic review of randomized controlled trials summarized the compelling evidence that antidepressants are efficacious in varied types of neuropathic pain (McQuay, Tramer, Nye, et al., 1996). Antidepressants are now identified as first-line analgesics in neuropathic pain guidelines (Dworkin, Backonja, Rowbotham, et al., 2003; Dworkin, O’Connor, Backonja, et al., 2007; Moulin, Clark, Gilron, et al., 2007). Anticonvulsants are another first-line choice for neuropathic pain and are discussed later in this section (see Chapter 23). Several excellent systematic reviews, some with related evidence-based guidelines for drug selection, provide additional support for the use of antidepressants in the management of neuropathic pain (Finnerup, Otto, McQuay, et al., 2005; Saarto, Wiffen, 2007; Kroenke, Krebs, Bair, et al., 2009). Data from another systematic review showed that there is no difference between antidepressants and anticonvulsants in the likelihood of achieving pain control (Chou, Carson, Chan, 2009).



Tricyclic Antidepressants (TCAs)


Evidence is compelling that the TCAs produce analgesia for a variety of chronic (persistent) pain syndromes including both neuropathic and other types of persistent pain (Argoff, Backonja, Belgrade, et al., 2006; Arnold, 2007; Hauser, Bernardy, Uceyler, et al., 2009; Dworkin, Backonja, Rowbotham, et al., 2003; Dworkin, O’Connor, Backonja, et al., 2007; Moulin, Clark, Gilron, et al., 2007; Perrot, Javier, Marty, et al., 2008; Tomkins, Jackson, O’Malley, et al., 2001; Verdu, Decosterd, Buclin, et al., 2008). The efficacy of the tertiary amine compounds has been demonstrated in a large number of controlled and uncontrolled trials (see each TCA listed below). Amitriptyline (Elavil), a tertiary amine, has an abundance of research showing efficacy and has been used for many years to treat a variety of types of persistent pain. Adverse effects are common, however, and the risk of more serious adverse effects, such as orthostatic hypotension, is relatively high (Curtis, Ostbye, Sendersky, et al., 2004; Dworkin, O’Connor, Backonja, et al., 2007).


Although research is more limited with the secondary amines, such as desipramine (Norpramin) and nortriptyline (Aventyl, Pamelor), they have also been shown to be efficacious in a variety of painful conditions and usually are better tolerated (American Geriatrics Society, 2002; Dworkin, Backonja, Rowbotham, et al., 2003; Dworkin, O’Connor, Backonja, et al., 2007; Gore, Dukes, Rowbotham, et al., 2006; Simon, Lipman, Caudill-Slosberg, et al., 2002). Some neuropathic guidelines recommend the use of a tertiary amine TCA only if a secondary amine TCA is unavailable (Dworkin, Backonja, Rowbotham, et al., 2003; Dworkin, O’Connor, Backonja, et al., 2007). This recommendation is particularly appropriate in high-risk populations, such as older adults who are at greater risk for antidepressant adverse effects, especially when they are administered in high doses and in combination with other CNS-acting medications (Wright, Roumani, Boudreau, et al., 2009). An increasingly popular alternative to the secondary amine TCAs is the SNRI antidepressants, all of which have a better toxicity profile than the TCAs (see adverse effects).


The best evidence for the use of TCAs for the treatment of neuropathic pain is summarized in several clinical reviews (Collins, Moore, McQuay, et al., 2000; Dobecki, Schocket, Wallace, 2006; Jensen, Finnerup, 2007; Dworkin, Backonja, Rowbotham, et al., 2003; Verdu, Decosterd, Buclin, et al., 2008). Agents in this class are useful for managing all types of dysesthesias (abnormal unpleasant sensations), such as burning, electrical-like, shock-like, shooting, and lancinating (stabbing). A Cochrane Collaboration Review of 61 randomized controlled trials documented the efficacy of TCAs and reported the following additional findings (Saarto, Wiffen, 2007):



• The number-needed-to-treat (NNT) when TCAs are studied as analgesics for varied types of neuropathic pain averages 3.6 (95% CI 3 to 4.5), which means that it is necessary to treat 3 to 4 patients to find one who gets at least a 50% reduction in pain; in other words, one-third of patients with neuropathic pain who take TCAs achieve moderate pain relief.


• Amitriptyline has been the best studied TCA, and in a range of doses up to 150 mg/day (10 studies, 588 patients), this drug has an NNT of 3.1 (95% CI 2.5 to 4.2).


• Studies of painful HIV-related neuropathy have not confirmed the efficacy of the TCAs.


• Analgesic doses for TCAs are typically less than antidepressant doses, and the effect on pain can be independent of any effect on depression.


• Although several small studies have suggested that analgesic efficacy correlates with dose, dose-response data have not been established; nonetheless, TCAs must be titrated in individual patients to identify responders and, within the group of responders, achieve the most effective dose (gradual titration also reduces the risk of adverse effects and is especially important in older patients).


• Across studies (N = 453), 13% of participants dropped out of active groups for a variety of reasons including intolerable adverse effects; discontinuation of dosing due to adverse effects is likely to be more prevalent in clinical populations, and prescribers usually attempt to select specific drugs based on relatively more favorable adverse effect profiles.



Amitriptyline


Amitriptyline (Elavil) is a tertiary amine TCA and has been extensively studied as an analgesic. The following are among the pain syndromes for which this drug has established analgesic efficacy:



• Postherpetic neuralgia (Argoff, Backonja, Belgrade, et al., 2006; Bowsher, 2003; Collins, Moore, McQuay, et al., 2000; Dubinsky, Kabbani, El-Chami, et al., 2004; Rowbotham, Reisner, Davies, et al., 2005)


• Painful diabetic neuropathy (Boulton, Vinik, Arezzo, et al., 2005; Collins, Moore, McQuay, et al., 2000; Duby, Campbell, Setter, et al., 2004; Max, Culnane, Schafer, et al., 1987; Max, Lynch, Muir, et al., 1992)


• Fibromyalgia (Arnold, 2007; Nishishinya, Urrutia, Walitt, et al., 2008; Hauser, Bernardy, Uceyler, et al., 2009; Heymann, Helfenstein, Feldman, 2001; Uceyler, Hauser, Sommer, 2008) (see also Hauser, Thieme, Turk, 2009)


• Migraine and other types of headache (Ashina, Bendtsen, Jensen, 2004; Descombes, Brefel-Courbon, Thalamas, et al., 2001; Keskinbora, Aydinli, 2008; Krymchantowski, Silva, Barbosa, et al., 2002)


• Arthritis (Frank, Kashini, Parker, et al., 1988; Katz, Rothenberg, 2005; Simon, Lipman, Caudill-Slosberg, et al., 2002)


• Central spinal cord injury pain (Cardenas, Warms, Turner, et al., 2002)


• Central post-stroke pain (Frese, Husstedt, Ringelstein, et al., 2006; Kumar, Kalita, Kumar, et al., 2009)


• Persistent facial pain (List, Axelsson, Leijon, 2003)


• Cancer-related neuropathic pain (Miaskowski, Cleary, Burney, et al., 2005; Ventafridda, Bonezzi, Caraceni, et al., 1987)


• Chemotherapy-induced neuropathy (Note: 50 mg/day was thought to be too low to produce positive effects) (Kautio, Haanpaa, Saarto, et al., 2008)


• Interstitial cystitis (van Ophoven, Pokupic, Heinecke, et al., 2004)


• As mentioned, antidepressants are not appropriate for treatment of acute pain because of the delay in time before appreciable analgesia. However, although not approved for use in the United States at the time of publication, a phase I trial of IV amitriptyline established the safety of a 25 mg to 50 mg preoperative infusion (Fridrich, Colvin, Zizza, et al., 2007). (See amitriptyline patient medication information, Form V-1 on pp. 759-760, at the end of Section V).



Desipramine


Desipramine (Norpramin) is a secondary amine TCA. It has relatively more effect on norepinephrine reuptake than amitriptyline and usually causes fewer adverse effects. (See desipramine patient medication information, Form V-5 on pp. 767-768, at the end of Section V). Clinical reviews and single studies have shown its efficacy in the following:





“Newer” Antidepressants


Evidence of analgesic efficacy is compelling for the drugs that are synaptic reuptake blockers of both serotonin and norepinephrine. The SNRIs have a better adverse effect profile than TCAs (Zin, Nissen, Smith, et al., 2008). Duloxetine (Cymbalta) has been most studied, and milnacipran (Savella), an SNRI recently released in the United States, also has been approved for the treatment of fibromyalgia pain. There is limited evidence that venlafaxine (Effexor) is analgesic and, as yet, no evidence in support of the newer desvenlafaxine (Pristiq).


Bupropion (Aplenzin, Budeprion, Wellbutrin) and mirtazapine (Remeron) are relatively older drugs and have structures and actions distinct from the TCAs and SNRIs. Both increase activity in the pathways that use biogenic amines, including serotonin, norepinephrine, and dopamine. Evidence of analgesia from these drugs is very limited, but they are sometimes considered for patients with persistent pain, particularly when a concurrent symptom, such as fatigue or insomnia, would benefit from targeted treatment.


Guidelines for the treatment of neuropathic pain that recommend the analgesic antidepressants as possible first-line or second-line drugs suggest that consideration be given to the use of the SNRIs over the TCAs because of a more favorable adverse effect profile (Dworkin, Backonja, Rowbotham, et al., 2003; Moulin, Clark, Gilron, et al., 2007). There have been no comparative effectiveness trials, and the decision to select one or another is based on risk assessment and best clinical judgment. The newer antidepressants are discussed in alphabetical order in the following paragraphs.



Bupropion


Bupropion (Aplenzin, Budeprion, Wellbutrin) is distinguished from the TCAs and SNRIs because it inhibits neuronal norepinephrine reuptake and, less potently, dopamine reuptake (Katz, Penella-Vaughn, Hetzel, et al., 2005). The drug can be useful in the management of neuropathic pain (Semenchuk, Davis, 2000; Semenchuk, Sherma, Davis, 2001), but was found ineffective for relief of non-neuropathic persistent low back pain (Katz, Pennella-Vaughan, Hetzel, et al., 2005). An extensive review suggested bupropion as an option for painful diabetic neuropathy (Duby, Campbell, Setter, et al., 2004), but guidelines list it as a drug with limited evidence for this condition (Argoff, Backonja, Belgrade, et al., 2006). Reported case series indicate that this agent can help relieve pain associated with persistent headache (Pinsker, 1998).


Bupropion has a low risk of somnolence and sexual dysfunction, adverse effects that may be limiting with other antidepressants. Some patients report increased energy that appears to be unrelated to mood effects. This has led to empirical use of this drug for fatigue.



Duloxetine


Duloxetine (Cymbalta) is an established analgesic based on the results of numerous controlled trials (Dworkin, Backonja, Rowbotham, et al., 2003; Kroenke, Krebs, Bair, 2009). In the United States, it is approved for the treatment of fibromyalgia, and randomized controlled studies have shown its effectiveness for this type of pain (Arnold, Lu, Crofford, et al., 2004; Arnold, Rosen, Pritchett, et al., 2005; Hauser, Bernardy, Ucelyler, et al., 2009). A large (N = 520) randomized controlled 6-month trial of patients with fibromyalgia with or without major depression demonstrated improvements in both pain severity and Patient Global Impressions of Improvement (PGI-I) scores regardless of whether or not the patients were depressed (Russell, Mease, Smith, et al., 2008). Others have observed similar findings (Arnold, Hudson, Wang, et al., 2009). A 1-year trial established the long-term safety and efficacy of duloxetine in 350 women with fibromyalgia (Chappell, Littlejohn, Kajdasz, et al., 2009).


A number of randomized controlled studies also report that duloxetine is efficacious for depression-associated pain (Brecht, Courtecuisse, Debieuvre, et al., 2007; Perahia, Pritchett, Raskin, 2006; Raskin, Wiltse, Siegal, et al., 2007). In older depressed patients, duloxetine can improve mood, cognition, and pain (Raskin, Wiltse, Siegal, et al., 2007). However, a meta-analysis of five randomized controlled trials observed a lack of consistency in research findings and suggested that reports of pain relief in patients with depression may be overestimated (Spielmans, 2008).


Duloxetine also is approved for treatment of painful diabetic neuropathy. Numerous randomized controlled trials have shown its efficacy for this type of pain (Goldstein, Lu, Detke, et al., 2005; Kajdasz, Iyengar, Desaiah, et al., 2007; Pritchett, McCarberg, Watkin, et al., 2007; Raskin, Pritchett, Wang, et al., 2005), and some guidelines recommend it as a first-line analgesic for this condition (Argoff, Backonja, Belgrade, et al., 2006). One study suggested that relatively high pain intensity, but no other variable (e.g., age, type and duration of diabetes, or severity of neuropathy), predicted the efficacy of duloxetine (Ziegler, Pritchett, Wang, et al., 2007). A meta-analysis concluded that duloxetine had efficacy and tolerability comparable to gabapentin and pregabalin in diabetic peripheral neuropathic pain (Quilici, Chancellor, Lothgren, et al., 2009).


A study conducted in the United Kingdom concluded that duloxetine is a cost-effective and efficacious agent for the pain of diabetic peripheral neuropathy (Beard, McCrink, Le, et al., 2008). Similar results were found in a study in the United States, in which patients who participated in a previous randomized controlled study of painful diabetic neuropathy were re-randomized for a 52-week trial of 60 mg of duloxetine compared with routine treatment, which most often included gabapentin, venlafaxine, or amitriptyline (Wu, Birnbaum, Mareva, et al., 2006). Duloxetine was found to be more cost-effective than routine treatment from both employer and societal perspectives, which included patients’ out-of-pocket expenses.


Other studies have shown that the benefits produced by duloxetine can be sustained over time (Mease, Russell, Kajdasz, et al., 2009; Russell, Mease, Smith, et al., 2008; Wernicke, Wang, Pritchett, et al., 2007) and that improved functional outcomes accompany analgesia (Armstrong, Chappell, Le, et al., 2007; Arnold, Lu, Crofford, et al., 2004; Arnold, Rosen, Pritchett, et al., 2005; Russell, Mease, Smith, et al., 2008; Sullivan, Benlety, Fan, et al., 2009; Wernicke, Wang, Pritchett, et al., 2007). In summary, these favorable data support recent guidelines for the treatment of neuropathic pain, which designate the SNRIs as either first-line analgesics (Dworkin, O’Connnor, Backonja, et al., 2007) or second-line analgesics (Moulin, Clark, Gilron, et al., 2007).


Duloxetine may be effective for central pain as well. An open-label study revealed beneficial effects of duloxetine for the treatment of pain associated with Parkinson disease (Djaldetti, Yust-Katz, Kolianov, et al., 2007).


Although an early review concluded that research does not provide convincing support for the use of antidepressants for musculoskeletal pain (Curatolo, Bogduk, 2001), later research calls for further evaluation of duloxetine for osteoarthritis (OA) pain (Sullivan, Bentley, Fan, et al., 2009). Patients in the latter study were given two weeks of placebo followed by 10 weeks of duloxetine. Self-reported function improved, and pain intensity was reduced 30% as measured on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) between 2 and 12 weeks of treatment. Similarly, improvements in pain (30%) and physical function were found in patients who received duloxetine in another randomized, placebo-controlled trial (Chappell, 2009). More and larger studies on the use of duloxetine for this type of pain are needed. (See duloxetine patient medication information, Form V-6 on pp. 769-770, at the end of Section V).



Milnacipran


Milnacipran (Savella) is another SNRI that has been used for many years in Europe and Japan and was approved for use in the United States in 2009 for the treatment of fibromyalgia (12.5 mg to 100 mg/day). A 15-week multicenter randomized, placebo-controlled trial (N = 1196) reported significant improvements in pain, physical functioning, and fatigue associated with fibromyalgia (Clauw, Mease, Palmer, et al., 2008). A 27-week randomized, placebo-controlled trial (N = 888) found similar improvements in pain, fatigue, cognition, and other functional domains in patients with fibromyalgia (Mease, Clauw, Gendreau, et al., 2009). The drug is well tolerated even at high doses (Vitton Gendreau, Gendreau, et al., 2004), and response to treatment is reported to have a durability of up to one year (Owen, 2008). An interesting case report described the complete resolution of phantom limb pain with the use of milnacipran (50 mg/day) (Sato, Higuchi, Hishikawa, 2008). Further research on the use of this drug for this and other types of pain is needed.



Mirtazapine


Mirtazapine (Remeron) is distinguished from the other antidepressants by its tetracyclic chemical structure. Its antidepressant efficacy is similar to the SSRIs, such as fluoxetine (Prozac) (Howland, 2008). A meta-analysis of 12 new-generation antidepressants concluded that mirtazapine is similar to venlafaxine and more efficacious than duloxetine, fluoxetine, and paroxetine (Paxil) for the treatment of depression (Cipriani, Furukawa, Salanti, et al., 2009). It may be better tolerated than TCAs with fewer anticholinergic effects.


Well-controlled trials that fully evaluate the analgesic effects of the drug are lacking at this time; however, a randomized, placebo-controlled trial in 10 healthy adults found that a single dose of mirtazapine (30 mg) significantly increased pain tolerance during electrical stimulation (Arnold, Vuadens, Kuntzer, et al., 2008). A 4-week prospective, open-label study of cancer patients reported rapid improvements in pain, nausea, sleep disturbance, depression, and quality of life (Kim, Shin, Kim, et al., 2008). However, a study of cancer patients with major depression, anxiety, or adjustment disorders found that mirtazapine was effective in resolving insomnia, anxiety, and depressive symptoms, but not pain (Cankurtaran, Ozalap, Soygur, et al., 2008). Mirtazapine has been suggested as an option for treatment of tension-type headaches (Bigal, Rapoport, Hargreaves, 2008). It was also reported to resolve postdural puncture headache, but the authors of this paper noted that the drug has unknown fetal effects and cannot be routinely recommended for the headache that follows inadvertent dural puncture in the laboring patient (Sheen, Ho, 2008). Preoperative administration of mirtazapine has been shown to reduce preoperative anxiety and postoperative nausea and vomiting (Chen, Lin, Ko, et al., 2008).



Venlafaxine


In a study of experimental pain, venlafaxine (Effexor) increased pain tolerance (Enggaard, Klitgaard, Gram, et al., 2001), and in a study of patients with neuropathic pain, the drug reduced hyperalgesia and temporal summation (repeated neuronal stimulation and action potentials) but not intensity and pain detection thresholds (Yucel, Ozyalcin, Talu, et al., 2005). Electrocardiogram (ECG) changes have been associated with venlafaxine, so cautious use in patients with high cardiovascular (CV) risk is recommended (Dworkin, Backonja, Rowbotham, et al., 2003). (See venlafaxine patient medication information, Form V-12 on pp. 781-782, at the end of Section V). Among the studies of venlafaxine for the treatment of pain are the following:




Selective Serotonin Reuptake Inhibitors (SSRIs)


The evidence of analgesic efficacy for both the TCAs and the SNRIs far exceeds the SSRIs. Favorable anecdotal reports of fluoxetine (Prozac) analgesia (Diamond, Frietag, 1989; Geller, 1989) were refuted in a controlled trial, which showed no benefit in patients with painful diabetic neuropathy (Max, Lynch, Muir, et al., 1992). Other studies of fluoxetine yielded mixed results. A double-blind comparison of fluoxetine, desipramine, and amitriptyline in patients with postherpetic neuralgia revealed that all three were analgesic; although fluoxetine produced the fewest adverse effects, the dropout rate during fluoxetine treatment was highest (Davies, Reisner-Keller, Rowbotham, 1996). Another controlled study of 59 patients with rheumatic pain revealed that both amitriptyline 25 mg and fluoxetine 20 mg produced significant pain relief compared with placebo during 4 weeks of treatment; fluoxetine was considered superior to amitriptyline because of fewer adverse effects (Rani, Naidu, Prasad, et al., 1996).


Paroxetine (Paxil), another SSRI, has some benefit in the control of pain from diabetic neuropathy (Sindrup, Gram, Brosen, et al., 1990), and while one study reported that the drug was effective in improving mood and reducing anxiety in 116 patients with fibromyalgia, its pain relieving properties were far less apparent (Patkar, Masand, Krulewicz, et al., 2007). In contrast, a later meta-analysis found strong evidence for both paroxetine and fluoxetine in reducing pain but just small effects for mood and no effects on fatigue and sleep (Hauser, Bernardy, Uceyler, et al., 2009).


Fewer clinical trials have specifically compared the efficacy of antidepressants as analgesics for cancer pain. Nonetheless, there are general recommendations to advocate for the use of TCAs and SRNIs rather than SSRIs for treatment of neuropathic pain syndromes caused by progressive cancer and cancer treatments (Dworkin, O’Connor, Backonja, et al., 2007).



Summary


Substantial evidence exists that antidepressant drugs (both TCAs and SNRIs) have analgesic effects for diverse types of persistent pain. Given the range of pain syndromes that are potentially responsive, it is appropriate to classify these drugs as nonspecific, multipurpose analgesics. These agents are especially useful for the treatment of neuropathic pain states. The strongest evidence of analgesic efficacy is found in the numerous controlled trials of the tertiary amine drugs, of which amitriptyline is the best studied. There is less abundant data to support efficacy for the secondary amine TCAs nortriptyline and desipramine. Nevertheless, guidelines recommend the use of a tertiary amine TCA only if a secondary amine is unavailable because of a more favorable adverse effect profile (Argoff, Backonja, Belgrade, et al., 2006; Dworkin, O’Connor, Backonja, et al., 2007).


Antidepressants with more norepinephrine selective actions are also analgesic, and very impressive data have been generated for the SNRIs, with evidence mounting for their role in the treatment of numerous pain syndromes. Clinical interest is less for SSRIs despite their relatively good adverse effect profile. Among the SSRIs, limited evidence supports the analgesic efficacy of paroxetine and fluoxetine, but data are equivocal or absent for the others.

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Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Multipurpose Adjuvant Analgesics

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