THE use of adjuvant analgesics in the management of pain is a “labor intensive” endeavor that includes careful patient selection, evaluating and selecting the best agent and dosing regimen, assessing response to treatment, and adjusting therapy to achieve the greatest benefit. All these activities are predicated on a systematic assessment of the patient, both initially and throughout the course of therapy. Over time, changes in pain, adverse effects, or any concerns regarding quality of life may lead to modifications in therapeutic approaches to managing pain.
Few studies actually capture the frequency with which adjuvant therapy is used. In one study on the use of treatment modalities, 723 community residents with moderate to severe pain were surveyed about their use of analgesics (Vallerand, Fouladbakhsh, Templin, 2005). Approximately 75% reported taking nonopioids, 15% reported taking opioids, and 11.6% reported taking adjuvant analgesics. Of concern, fully 28% were taking drugs for pain but had not informed their primary care providers. This finding underscores the importance of patient education about the need for communication with the health care provider who prescribes their analgesics. The safe prescription of the adjuvant analgesics depends on accurate information about all the drugs taken by the patient (see the discussion of patient education at the end of Section V).
The selection of a specific adjuvant analgesic is usually based on the nature and characteristics of pain and the presence of other symptoms and co-morbidities. For example, an early trial of an analgesic antidepressant is justified by the existence of a co-morbid depression, which would be considered a separate target for this therapy.
Drug selection also may be influenced by the results of specific studies and accumulated clinical experience. For example, there are both controlled trials and several decades of experience suggesting the efficacy of carbamazepine in trigeminal neuralgia, and patients with this disorder often are offered a trial of this drug first. Similarly, patients with fibromyalgia usually are considered for a trial of the drugs that have been studied and are now approved for this condition, such as pregabalin and duloxetine.
In most circumstances, both the existing data and experience are insufficient to narrow the choice of drug substantially. Many options exist, and drug selection is based on guidelines or other factors; if one drug fails to provide adequate pain relief, others may be tried. In short, most of the therapeutic process involving the adjuvant analgesics follows an “informed trial-and-error” strategy in which drugs are offered in sequential trials based on the current evidence base, clinical experience, and other factors, such as age, co-existing medical conditions, prior response to a particular drug, issues with convenience and adherence to therapy, cost and availability of agents, and access to care and follow-up treatment. Decisions should be thoughtfully determined by an examination of the potential benefits and risks associated with therapy (Gatchel, Okifuji, 2006).
Cost comparison research is largely lacking, and the complex issue of cost-effectiveness usually ends with a decision influenced by the need for out-of-pocket expenses (a so-called cost-minimization strategy). A more sophisticated analysis involves assessment of pain intensity and distress, drug options, dosing regimen, likelihood of adherence, ancillary costs (e.g., other medications needed to control the adverse effects of the analgesics), and third-party payer influence (Gore, Sadosky, Tai, et al., 2007; O’Connor, Noyes, Holloway, 2007; Tarride, Gordon, Vera-Llonch, et al., 2006). The limited information about these factors at the start of therapy typically results in a prediction about overall costs that is highly tentative. An excellent cost analysis of the effect of pregabalin in the treatment of radiculopathy in the primary care setting found that pregablin alone or as an add-on therapy at doses within the recommended range significantly reduced pain, which translated into meaningful reductions in the use of both health care and non–health care resources (Saldana, Navarro, Perez, et al., 2010). The increases in drug cost were offset by a significant decrease in the costs associated with other components of health care, such as complementary tests, medical visits, and nondrug therapies.
Patient preference also is critical to consider in drug selection. Patients may express preferences that are idiosyncratic (e.g., knowledge of a family member who experienced benefit or adverse effects from a drug) or informed by factors that may influence their ability to tolerate a drug or adhere to therapy. Collaborative decision making around the use of therapeutic options for pain relief increases the likelihood that the patient will be adherent with the treatment plan (Manias, Williams, 2008).
The adjuvant analgesics are heterogeneous, and dosing regimens vary. A few of the drugs are available as parenteral formulations, which can be used in monitored environments and administered at full doses promptly (e.g., a relatively large, intravenous [IV] loading dose of a corticosteroid, lidocaine, or valproate in the management of severe neuropathic pain).
In the more common scenario of oral drug administration in the ambulatory setting, low initial doses and gradual dose escalation may avoid early adverse effects or allow tolerance or adjustment to the adverse effects. In medically ill patients, this precaution is especially appropriate when adjuvant analgesics are initiated. When low doses and gradual titration to therapeutic effects are employed, it is easier to optimize therapy and balance pain relief with adverse effects. In some cases, patients must be forewarned that onset of analgesia with adjuvant drugs is likely to be delayed. Otherwise, patients may become discouraged and stop taking the drug.
There is considerable variability among individuals in their response to adjuvant analgesics, including agents within the same class. While specific patient characteristics (e.g., advanced age, co-existing organ dysfunction or failure, and inherent differences in the ways patients metabolize and respond to drugs) may increase the likelihood of some common adverse effects, it is nonetheless true that neither beneficial nor unfavorable effects from any specific medication can be reliably predicted. The potential utility of adjuvant analgesics may only be established through repeated trial and error, allowing sufficient time to determine whether an adjuvant agent is likely to reduce pain.
The existence of significant intraindividual variation in the response to the large group of adjuvant analgesics must be explained to patients. If a treatment regimen is not successful, it is also critical that patients are aware of other options that can be tried. Frustration with the delay in finding an effective drug and the time required with each drug to explore the dose range should be acknowledged, but patients also should be encouraged to hold on to hope that a useful therapy will be found.
As noted, a medical or psychiatric co-morbidity may be an independent target for therapy, and as such, help guide the decision to try one type of adjuvant analgesic over another. Co-morbidities also must be recognized as potential impediments to the safe use of these drugs. For example, patients with pulmonary disease may be susceptible to the sedating effects of drugs and be placed at increased risk for respiratory problems or respiratory depression with the addition of sedating adjuvant analgesics. Debilitated patients are more prone to adverse effects such as sedation or confusion that may lead to falls or further functional decline. Renal and hepatic dysfunction can interfere with drug metabolism and excretion. Older adults may already have complex medication regimens for the management of other health problems. Therefore, it is important to identify potential drug-drug interactions that could alter risk assessment.
Teratogenic effects have been reported with some of the adjuvant analgesics, but little data exist to fully assess safety. Many have warnings against their use during pregnancy or recommendations for careful consideration of risk versus benefit (Lacy, Armstrong, Goldman, et al., 2008). For example, although the risk/benefit ratio is not defined for steroid use during the second and third trimesters of pregnancy, they should be avoided during the first trimester because they are associated with teratogenic effects (Hess, Aleshi, 2008).
Anticonvulsants (e.g., carbamazepine and valproic acid) have been studied during pregnancy primarily in women with epilepsy. There is twice the risk of congenital defects, such as cleft palate and congenital heart disease, in offspring of women who take them during pregnancy compared with the general population (Viscomi, Rathmell, 1998). Phenytoin should be avoided, as use is associated with a 7% increased risk of fetal hydantoin syndrome (microencephaly, mental deficiency, and craniofacial abnormalities). Tricyclic antidepressants (TCAs) are generally not recommended during pregnancy, but their benefit may outweigh the risk in some patients (Viscomi, Rathmell, 1998). First-trimester exposure to benzodiazepines (e.g., diazepam) may also carry an elevated risk of fetal congenital malformation, although this is poorly studied (Viscomi, Rathmell, 1998). Maternal benzodiazepine use can cause sedation and poor feeding in nursing infants so should be avoided.
Local anesthetics are generally considered safe, but due to progesterone-induced sensitivity to local anesthetics, dose is often reduced (Hess, Aleshi, 2008). All local anesthetic drugs cross the placenta, and the factors that influence maternal toxicity will influence fetal toxicity. Maternal administration of lidocaine and mepivacaine has been implicated in reduction of muscle tone in the neonate, but this appears to be less of a problem with bupivacaine because it binds to maternal plasma proteins better (Woods, DiFazio, 1995). Local anesthetics are considered safe during breast-feeding. Clonidine also is thought to produce minimal effects on infants during pregnancy and breast-feeding (Viscomi, Rathmell, 1998).
Women are advised to discuss the need to discontinue or avoid some of the adjuvant analgesics prior to becoming pregnant or breast-feeding whenever possible. Alternate methods for managing pain may be warranted in patients with underlying persistent pain and can be implemented in advance (e.g., opioid administration for some types of neuropathic pain; see Section IV). Clearly, more research is needed regarding the safe use of adjuvant analgesics during pregnancy and breast-feeding.
Broad acceptance of a role in pain management for the adjuvant analgesic drugs is premised on the growing importance of multimodal treatment for persistent (chronic) pain. As discussed in Section I, multimodal therapy is a relatively new concept, first proposed in the early 1990s and applied primarily to the treatment of acute pain and prevention of persistent postsurgical pain (Buvanendran, Kroin, 2009; Buvanendran, Kroin, Della Valle, et al., 2010; Gartner, Kroman, Callesen, et al., 2008; Kehlet, Jensen, Woolf, 2006; Milch, 2005; Pasero, 2003a; Polomano, Rathmell, Krenzischek, et al., 2008; Tang, Evans, Chaput, et al., 2009). Multimodal therapy involves the use of two or more classes of analgesics to target different pain mechanisms in the peripheral or central nervous system (see Section I). It relies on the thoughtful and rational combination of analgesics to maximize pain relief and prevent analgesic gaps that may lead to worsening pain or unnecessary bouts of uncontrolled pain (Carr, Reines, Schaffer, et al., 2005).
A multimodal approach may allow lower doses of each of the drugs in the treatment plan, and lower doses have the potential to produce fewer adverse effects (Ashburn, Caplan, Carr, et al., 2004; Brodner, Van Aken, Hertle, et al., 2001). Further, multimodal analgesia can result in comparable or greater pain relief than can be achieved with any single analgesic (Busch, Shore, Bhandari, et al., 2006; Butterfield, Schwarz, Ries, et al., 2001; Cassinelli, Dean, Garcia, et al., 2008; Huang, Wang, Wang, et al., 2008; White, 2005). In the setting of postoperative pain, the use of combination therapy to prevent both inflammatory and neuropathic pain is likely to yield the best immediate results and also offers the promise of reducing the incidence of prolonged or persistent postsurgical pain (Kehlet, Jensen, Woolf, 2006).
The multimodal strategy also has a role in the management of persistent pain. This is true in all of the various practice settings, including the emergency department (Baker, 2005), outpatient treatment sites (Gatchel, Okifuji, 2006), and settings providing specialist palliative care (Soares, Chan, 2007). The complex nature of the many persistent pain conditions indicates the need for appropriate combinations of analgesics to target different underlying mechanisms (Argoff, Albrecht, Irving, et al., 2009).
Multimodal therapy also is a useful strategy for addressing the common problem of symptom distress related to symptoms other than pain. Patients with acute or persistent pain often experience additional symptoms, which as noted, may influence the decision to try one of the adjuvant analgesics over another. More broadly, the experience of multiple symptoms also may guide the use of multiple drugs, some of which are targeted to distressing conditions, such as insomnia, that accompany pain and may be a factor in worsening it (Gan, Meyer, Apfel, et al., 2003; 2007; Gartner, Kroman, Callesen, et al., 2008).
The term polypharmacy carries a negative connotation, in contrast to multimodal therapy or combination therapy. Whereas multimodal therapy is based on rational combinations of analgesics with differing underlying mechanisms to achieve the most benefit in pain control, polypharmacy suggests the use of drug combinations that are irrational and less effective or safe than a regimen that has fewer or different agents.
Polypharmacy is most likely to occur in populations and settings in which rational multimodal therapy is appropriate and encouraged. For example, in the palliative care setting, adjuvant analgesics are typically administered to patients who are already receiving multiple drugs. Although complex regimens are widely regarded as appropriate in the care of terminally ill patients, the potential for additive or unpredictable adverse effects must be anticipated whenever an adjuvant is added to an existing drug regimen.
Polypharmacy is often a problem in older adults who may have complex medical conditions, are more susceptible to adverse effects of medications and combinations of drugs, and may be less adherent to complex medication schedules (American Geriatrics Society, 2002; Ruoff, 2002). A longitudinal cohort study of 2737 adults age 65 years and older found an association between cognitive decline and the combined use of medications that act on the central nervous system (CNS), especially when taken in high doses (Wright, Roumani, Boudreau, et al., 2009). The researchers emphasized the importance of careful drug selection and using the lowest effective doses, especially when treating the co-morbidities of pain and psychiatric conditions in older adults. These principles apply to all patients with pain.
Many of the adjuvant analgesics are metabolized in the liver by the cytochrome P450 system of isoenzymes (Virani, Mailis, Shapiro, et al., 1997) (see Chapter 11 for more on this). This also raises concern about the potential for drug-drug interactions. Patients may take drugs that either induce or block specific isoenzymes. An enzyme that is induced can metabolize substrates faster or more completely, leading to plasma drug concentrations less than would be expected at a specific dose. Conversely, an enzyme that is blocked could slow metabolism and lead to higher than anticipated concentrations of newly added drugs.
There are many examples of potentially problematic interactions. Some chemotherapeutic agents (Novy, Stupp, Rossetti, 2009; Yap, Chui, Chan, 2008) and oral antidiabetic agents (Schiltmeyer, Kropeit, Cawello, et al., 2006) may interfere with some analgesics. Concurrent administration of antidepressants that are substrates for the CYP2D6 enzyme (e.g., serotonin norepinephrine reuptake inhibitors [SNRIs] and TCAs) can increase tricyclic levels and lead to seizure activity (Lamoure, 2007). Clinicians who care for individuals with pain must become familiar with each drug’s metabolism and the way the various drugs interact with the cytochrome P450 enzymes to provide safe and effective therapy. Patients must be told to report adverse effects promptly, and in some cases serum drug concentrations should be closely monitored to prevent toxicity, such as in patients who take multiple other medications.
Polypharmacy may lead to negative effects that are more subtle than potentially dangerous plasma levels of a drug. When a patient is receiving opioid and nonopioid analgesics, for example, the decision to initiate or continue an adjuvant analgesic must be based on careful assessment of patient outcomes and a clear understanding of the goals of therapy. If adjuvant medications yield demonstrable benefits without adverse effects that impair function or quality of life, then there may be ample justification for adding or continuing them. This is included among the benefits of a rational multimodal therapeutic strategy. Attempting to achieve additional pain relief at the cost of inducing untoward adverse effects such as sedation or cognitive impairment is not acceptable practice in patients who desire a more active lifestyle but may be appropriate for those who seek comfort as the only goal of treatment.
As described in Section IV, opioids are first-line analgesics for severe acute pain and moderate to severe persistent pain related to active cancer or other advanced illnesses (Hanks, Cherny, Fallon, 2004; Lussier, Portenoy, 2004). Opioids remain controversial in the treatment of persistent noncancer pain, and first-line use should be considered only when the severity of the pain or the urgency of treatment is such that aggressive opioid dosing is perceived to be the most likely way to help promptly (Dworkin, Backonja, Rowbotham, et al., 2003).
For patients with persistent noncancer pain, the NSAIDs or adjuvant analgesics are usually viewed as the first-line therapies. For those with acute postoperative pain, an adjuvant analgesic, such as an anticonvulsant, may be considered for preoperative or immediate postoperative administration, as an adjunct to an opioid regimen.
The adjuvant analgesics, as a group, are considered to be adjunctive to opioid therapy in the setting of moderate to severe pain related to active cancer or other serious illnesses, because extensive experience supports the conclusion that analgesic effects from opioids are both more reliable and faster in onset (Lussier, Huskey, Portenoy, 2004; Lussier, Portenoy, 2004). This observation has not been contradicted in the literature, which generally lacks well-designed, controlled trials in cancer populations. Slower onset of analgesic effects for most adjuvant agents and the need to initiate therapy at low doses to avoid adverse effects also may be responsible for achieving inconsistent benefits (Lussier, Portenoy, 2004).
Survey data demonstrate satisfactory pain relief within days for 70% to 90% of cancer patients who receive opioid therapy (Lussier, Huskey, Portenoy, 2004; Lussier, Portenoy, 2004; Ripamonti, Dickerson, 2001); however, more time may be needed to adjust the dose of an adjuvant analgesic and judge its effects (Maizels, McCarberg, 2005; Saarto, Wiffen, 2007). Studies of TCAs show that these drugs may require treatment for weeks to obtain optimal results; with adequate dosing, pain may be relieved by more than 50% in 50% to 75% of patients with neuropathic pain (Lussier, Huskey, Portenoy, 2004; Lussier, Portenoy, 2004).
Although the extant data are insufficient to conclude that all adjuvant analgesics perform less well than an opioid in every type of pain experienced by cancer patients, the safest and most efficient approach in patients with serious medical illness usually involves the addition of an adjuvant analgesic to an opioid regimen that is not producing adequate analgesia despite dose escalation to limiting adverse effects (Lussier, Huskey, Portenoy, 2004; Lussier, Portenoy, 2004). Unless another indication for an earlier trial exists (e.g., a co-morbidity that may also respond to the drug, a history of problems with opioids, or a type of pain that may be particularly responsive to a specific adjuvant), it is reasonable to initiate treatment with the adjuvant analgesic after the opioid dose has been optimized. In practice, some clinicians attempt to improve patient response by initiating therapy with an opioid and an adjuvant analgesic concurrently, but it must be recognized that this approach increases the risk of additive toxicity and may make it difficult to determine which drug is responsible for the resulting analgesia or adverse effects.
The adjuvant analgesic group is the largest group of analgesics, representing drugs that vary widely in their underlying mechanisms of action and indications for use. Selection of the optimal adjuvant analgesic is strongly influenced by the type of pain to be treated as well as a number of patient factors, including age, coexisting disease, and potential for drug-drug interactions. Cost of the drug is another major consideration. Almost all of the adjuvant analgesics require titration of dose to find a balance between pain relief and adverse effects.