Terminology and Subtypes

Adjunctive analgesics is a term used to describe medications that can be used for pain relief but whose primary indication is not related to pain. This term is also used to differentiate these types of analgesics from the more commonly used drug classes such as simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants, which are collectively termed common analgesics in this textbook and discussed in Chapter 11, as well as opioid analgesics, which are discussed in Chapter 12. Adjunctive analgesics are also known as adjuvant analgesics, nontraditional analgesics, or unconventional analgesics.

Adjunctive analgesics for chronic low back pain (CLBP) discussed in this chapter include the following two main drug classes, each of which contains several subclasses and specific medications: antidepressants (Figure 13-1) and antiepileptics.^1,2

Figure 13-1 Molecular structures for three different adjunctive analgesics.

Numerous other types of medication are occasionally used for symptomatic relief of painful conditions such as CLBP, including corticosteroids, topical anesthetics, cannabinoids, α₂-adrenergic agonists, and N-methyl-D-aspartate (NMDA) receptor antagonists.^1,2 Although these may also be considered adjunctive analgesics, they will not be discussed in this chapter.

Antiepileptics

Antiepileptics are also known as anticonvulsants. There are three main categories of antiepileptics, named in chronological order of discovery: first generation, second generation, and third generation.^6–8

First Generation

First-generation antiepileptics include carbamazepine, valproic acid, phenytoin, phenobarbital, primidone, ethotoin, ethosuximide, and methsuximide.

Second Generation

Second-generation antiepileptics include gabapentin, felbamate, tiagabine, levetiracetam, zonisamide, fosphenytoin, vigabatrin, pregabalin, topiramate, lamotrigine, and oxcarbazepine.

Third Generation

Third-generation antiepileptics include acetazolamide, lacosamide, rufinamide, and stiripentol.

Tables 13-1 and 13-2 list specific medications in each of these drug classes, as well as their trade names and indications.

TABLE 13-1 Medications and Approved Indications by Type of Antiepileptic Adjunctive Analgesic

TABLE 13-2 Medications and Approved Indications by Type of Antidepressant Adjunctive Analgesic

History and Frequency of Use

Several types of medications have been used to manage symptoms of low back pain (LBP), including many that are no longer used (e.g., colchicine).⁹ Use of new medications to manage LBP often begins anecdotally, with clinicians observing their effects for other indications and extrapolating those results to how they may impact LBP. This appears to be the case with adjunctive analgesics, which have been used for at least 4 decades to manage LBP but appear to have grown in popularity in the past decade.¹⁰ An increasing use of adjunctive analgesics is likely due to a lack of long-term results when using traditional analgesics, prompting clinicians to try other approaches for patients with persistent symptoms. The use of antiepileptic medications as adjunctive analgesics for CLBP likely arose from their US Food and Drug Administration (FDA) approval for neuropathic pain conditions such as postherpetic neuropathy (PHN) and diabetic peripheral neuropathy (DPN).

Medications are the most commonly recommended option for managing LBP and are prescribed to approximately 80% of patients presenting to a primary care provider.¹¹ There are wide variations in prescribing patterns and little agreement among primary care providers on the optimal medication regimen for LBP; one third of patients with LBP are prescribed more than one medication. It was reported in 1985 that TCAs were prescribed by primary care providers to approximately 2% of patients presenting with LBP.⁹ More recently, it was reported that 12% of patients in Belgium with LBP were prescribed antidepressants, and 2% were prescribed antiepileptics.¹² Use of antidepressants and antiepileptics for LBP appears to be higher in older adults; similar figures for adults older than age 60 were 17% and 3%, respectively. A study in Sweden asked 302 patients who presented to 16 physicians at 14 randomly selected outpatient clinics to complete questionnaires on health care resource use in the past 6 months.¹³ Antidepressants were the fifth most commonly used class of medication, reported by 8% of patients.

Practitioner, Setting, and Availability

Adjunctive analgesics require a prescription and can be dispensed by any physician with a medical license. This intervention is widely available in a variety of settings throughout the United States, including private medical practices and hospitals. Although they can be used in primary care settings, adjunctive analgesics for CLBP are perhaps best prescribed in secondary care settings. Pain management or other nonsurgical specialists may best be suited to confirm that radicular pain is neuropathic in nature, select amongst the many available adjunctive analgesics, monitor possible interactions between concomitant use of adjunctive and simple or opioid analgesics, assess adverse events commonly reported with adjunctive analgesics, and determine appropriate use of non-medication interventions that may be required for optimal outcomes.

Procedure

Management of CLBP with adjunctive analgesics involves consultation with a physician who will take a detailed medical and LBP-focused history, and inquire about current medication use. If deemed appropriate, the physician will then prescribe an adjunctive analgesic along with instructions about dosage, timing, side effects, and interactions with other medication; this information may also be provided by the dispensing pharmacist. A follow-up appointment will likely be scheduled within a few weeks so that the physician can determine whether the adjunctive analgesic is achieving the desired effect, adjust the dosage if necessary, change the medication in favor of another adjunctive analgesic or different class of medication if required, and provide education about other strategies for improving CLBP.

Regulatory Status

The adjunctive analgesics discussed in this chapter are all approved by the FDA for other primary indications and are therefore used off-label for CLBP. These medications are only available by prescription (Figure 13-2).

Figure 13-2 Adjunctive analgesics are only available by prescription.

(© Gold Standard, Inc.)

Mechanism of Action

The use of adjunctive analgesics for CLBP is based on its presumed etiology, which can broadly be divided into nociceptive or neuropathic pain.^14,15 Nociceptive pain stems from any tissue injury that initiates a nociceptive signal carried by a nerve, and is thought to account for the vast majority of patients with CLBP. Neuropathic pain stems specifically from injury to the nerve itself, which likely contributes to the clinical presentation in only a small fraction of patients with CLBP. Nociceptive CLBP need not be confined to the lumbosacral area and may refer pain along the dermatomal distribution of a spinal nerve root or peripheral nerve. Neuropathic CLBP is radicular in nature and may be felt all along the area of sensory innervation for a spinal or peripheral nerve. The etiology of nociceptive pain is multifaceted and may result from any number of mechanisms of injury to the lumbosacral area, whereas the etiology of neuropathic pain is often due to inflammation secondary to infection, autoimmune, metabolic, or neurologic disorders. The distinction between neuropathic and nociceptive pain is crucial with respect to adjunctive analgesics for CLBP because some medications are intended solely for neuropathic pain and may have no effect in nociceptive pain.¹⁶

Table 13-3 compares some of the basic characteristics for nociceptive and neuropathic pain.

TABLE 13-3 Characteristics of Neuropathic and Nociceptive Pain

Various adjunctive analgesics work along different sections of the pain pathway.¹⁷ Pain is activated through a veritable cornucopia of peripheral receptors, often producing a soup of inflammatory mediators that can perpetuate or amplify the nociceptive signal (e.g., bradykinin, leukotrienes, substance P). In patients with chronic pain, it is hypothesized that a windup phenomenon occurs in the dorsal horn, resulting in increased activity of NMDA receptors and activation of voltage-gated calcium channels. If this state endures, central sensitization via modulation of the spinal cord may eventually develop, with descending inhibition of the pain pathway at the spinal cord level. This phenomenon can slowly decrease the threshold required to trigger a nociceptive signal, resulting in greater and more frequent pain.^14,18

Indication

Many adjunctive analgesics have been investigated for the treatment of chronic neuropathic pain in general; relatively few studies have focused specifically on CLBP. Most of the literature on this topic relates to the use of adjunctive analgesics for neuropathic pain secondary to conditions such as painful polyneuropathy (PPN), DPN, PHN, central poststroke pain, trigeminal neuralgia, or postmastectomy pain. The use of adjunctive analgesics for CLBP therefore requires extrapolating results from other indications that differ from CLBP in varying degrees. It should be noted that the use of adjunctive analgesics for CLBP is a secondary indication for these medications, which also possess primary indications that may be useful in some patients with CLBP. For example, patients with neuropathic or nociceptive CLBP who also have associated depression may benefit from TCAs, SSRIs, or SNRIs. Similarly, patients with CLBP who report insomnia associated with anxiety about their physical discomfort may benefit from antidepressants with known sleep-inducing properties, such as trazadone or doxepin. Although the indication for prescribing adjunctive analgesics in such cases is not primarily CLBP, symptoms of CLBP may also improve with their use.

Assessment

Before receiving adjunctive analgesics, patients should first be assessed for LBP using an evidence-based and goal-oriented approach focused on the patient history and neurologic examination, as discussed in Chapter 3. Additional diagnostic imaging or specific diagnostic testing is generally not required before initiating these interventions for CLBP. Prescribing physicians should also inquire about medication history to note prior hypersensitivity/allergy or adverse events with similar drugs, and evaluate contraindications for these types of drugs. Clinicians may also wish to order a psychological evaluation if they are concerned about the potential for medication misuse or potential for addiction in certain patients. Diagnostic imaging or other forms of advanced testing is generally not required before administering adjunctive analgesics for CLBP.

Clinical Practice Guidelines

Systematic Reviews

Antidepressants

Cochrane Collaboration

The Cochrane Collaboration conducted an SR in 2008 on antidepressants for nonspecific LBP.³³ A total of 10 RCTs were included that compared antidepressants with placebo; 9 included patients with CLBP, while 1 did not specify the duration of LBP.^34–43 Overall, the review found inconsistent evidence regarding antidepressants on pain relief in CLBP, with a meta-analysis of six small RCTs giving a standard mean difference (SMD) of −0.04 (95% CI −0.25 to 0.17). The review also concluded that there is no consistent evidence that antidepressants reduce depression in CLBP patients, or that antidepressants improve functional status in LBP patients. Furthermore, there was no difference between two types of antidepressants (TCAs and SSRIs) and placebo in pain relief.

American Pain Society and American College of Physicians

An SR was conducted in 2007 by the American Pain Society and American College of Physicians CPG committee on medication for acute and chronic LBP.¹¹ That review identified 3 SRs related to antidepressants and LBP, which included 10 unique RCTs.^44–46

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