**6. Adjuvant medications**

Medications that fall into the adjuvant medication category have a unique place in therapy. These medications typically fall into two categories and can be added at any point in therapy (any step of the WHO's analgesic ladder). They should be used to tailor treatment and are a mainstay in the targeted treatment of the individual. The two categories are drugs that target neuropathic pain and drugs that target somatic pain through an indirect mechanism [8, 10]. When initiating an adjuvant medication, it should have a clear target and purpose to aid in decreasing pain. Adjuvants should not be used simply to lower opioid requirements, espe‐ cially in patients, on lower doses, with minimal side effects as most adjuvants are not benign and many have severe side effects themselves [27].

Neuropathic pain is a type of pain that originates through a dysfunction in the peripheral or central nervous system [28, 29]. It is estimated to effect up to 7–8% of the general population in Europe and is often so severe that it is disabling to patients. It can be caused by several dif‐ ferent disease processes including chronic radiculopathy and has a high incidence in low back pain caused by inflammatory causes.

Gabapentin and pregabalin exert their mechanism of action through binding to voltage‐gated calcium channels and result in a decrease in release of the neurotransmitters glutamate and substance P [27, 28]. These agents are commonly considered first‐line agents due to their high efficacy and a relatively benign side effect profile. Efficacy seems to increase as dose increases, but so do side effects. Most commonly, patients experience dizziness, sedation, peripheral edema and dry mouth [30]. Both agents can aid in sleep disturbances, and pregabalin has a mild anxiolytic effect as well. These agents have also been used in acute pain and are now recommended in the postoperative setting with more clinicians claiming these agents should be used as true analgesics and not as adjuncts [31].

Antidepressants can alter pain through several different mechanisms. These include modula‐ tion of monoamine activation, interacting with opioid pathways, inhibiting descending pain pathways and blocking ion channels that are important in pain transmission [27]. Tricyclic antidepressants (TCAs) have the most robust evidence to support their use in neuropathic pain. While the exact mechanism is unknown, it is likely mediated through blocking the reuptake of norepinephrine. These agents are antagonistic at N‐methyl‐D‐aspartate (NMDA) receptors and may have a roll at reducing hyperalgesia caused by central windup. Agents in this class include the secondary amines nortriptyline and desipramine and tertiary amines amitriptyline and imipramine. When compared to each other, no agent has been found to be superior to another. Despite this, nortriptyline and desipramine are typically considered the preferred agents due to better side effect profile. TCAs are associated with increased risk for sedation, orthostatic hypotension, dry mouth, constipation, urinary retention and cognitive impairment especially in the elderly [15, 23, 28].

used. Additionally, if a clinician commonly prescribes NSAIDs, they should be diligent in following new evidence on efficacy and safety of individual agents to assist them in select‐ ing the most ideal one. When considering a patient's analgesic regimen, NSAIDs are a viable first‐ or second‐line treatment choice if the risks for drug‐related complications are low [1, 6]. In relation to the WHO's stepwise ladder, adding a NSAID is especially useful if a patient has an acute increase in pain (acute injury, worsening breakthrough pain, etc.) and even more so if the acute pain process has an inflammatory component. Ideally, when the acute pain event is resolved or mitigated, the clinician can shift back down the pain ladder and remove the

Medications that fall into the adjuvant medication category have a unique place in therapy. These medications typically fall into two categories and can be added at any point in therapy (any step of the WHO's analgesic ladder). They should be used to tailor treatment and are a mainstay in the targeted treatment of the individual. The two categories are drugs that target neuropathic pain and drugs that target somatic pain through an indirect mechanism [8, 10]. When initiating an adjuvant medication, it should have a clear target and purpose to aid in decreasing pain. Adjuvants should not be used simply to lower opioid requirements, espe‐ cially in patients, on lower doses, with minimal side effects as most adjuvants are not benign

Neuropathic pain is a type of pain that originates through a dysfunction in the peripheral or central nervous system [28, 29]. It is estimated to effect up to 7–8% of the general population in Europe and is often so severe that it is disabling to patients. It can be caused by several dif‐ ferent disease processes including chronic radiculopathy and has a high incidence in low back

Gabapentin and pregabalin exert their mechanism of action through binding to voltage‐gated calcium channels and result in a decrease in release of the neurotransmitters glutamate and substance P [27, 28]. These agents are commonly considered first‐line agents due to their high efficacy and a relatively benign side effect profile. Efficacy seems to increase as dose increases, but so do side effects. Most commonly, patients experience dizziness, sedation, peripheral edema and dry mouth [30]. Both agents can aid in sleep disturbances, and pregabalin has a mild anxiolytic effect as well. These agents have also been used in acute pain and are now recommended in the postoperative setting with more clinicians claiming these agents should

Antidepressants can alter pain through several different mechanisms. These include modula‐ tion of monoamine activation, interacting with opioid pathways, inhibiting descending pain pathways and blocking ion channels that are important in pain transmission [27]. Tricyclic antidepressants (TCAs) have the most robust evidence to support their use in neuropathic pain. While the exact mechanism is unknown, it is likely mediated through blocking the reuptake of norepinephrine. These agents are antagonistic at N‐methyl‐D‐aspartate (NMDA)

NSAID from the regimen.

**6. Adjuvant medications**

192 Pain Relief - From Analgesics to Alternative Therapies

and many have severe side effects themselves [27].

be used as true analgesics and not as adjuncts [31].

pain caused by inflammatory causes.

TCAs are not the only antidepressants that have been looked at for the treatment of neuro‐ pathic pain. SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) have also been evaluated. Even though the SSRIs citalopram and paroxetine have shown efficacy in treating neuropathic pain, they are typically not as preferred compared to TCAs and SNRIs because they are less efficacious [28]. Previously, TCAs had been preferred due to more evidence and lower costs. However, costs of both venlafaxine and duloxetine have decreased recently and use has increased. Some guidelines even support their use as first‐line agents [29]. Of the two, duloxetine seems to be preferred because it is associated with less hypertension and is well tolerated in the elderly [16, 28, 29]. Patients should be counseled on the fact that treat‐ ing pain with antidepressants can take up to 2.5 weeks to reach their full effect and this can decrease compliance.

Other common adjuvant medications commonly added to analgesic regimens include muscle relaxants, corticosteroids, local anesthetics and topical agents [27, 32]. Muscle relaxants as a group have varying mechanisms of action, some of which are not fully understood. These agents may be considered for acute pain relief, but have very limited data to support con‐ tinued use. They should only be used in patients who have increased somatic pain due to spasticity. The primary side effect of this drug class is central nervous system adverse effects (sedation, fatigue, dizziness, etc.), but because these drugs are not related in mechanism, they each have their own safety profiles. Due to the lack of data and risk for severe side effects (e.g., hepatotoxicity of dantrolene) use of skeletal muscle relaxants for back pain not associ‐ ated with severe spasticity is discouraged.

Topical lidocaine may be of an advantage for patients who complain of localized neuropathic pain [28]. Lidocaine decreases the frequency of Na+ channel opening, thereby decreasing pain transmission. When it is used topically, systemic absorption is decreased, which makes sys‐ temic adverse reactions very rare. Evidence for use in low back pain is lacking, but its use should be considered if a patient complains of localized neuropathic pain.

Patients who suffer from chronic low back pain are sometimes prescribed corticosteroids. Many different doses of prednisone and dexamethasone have been studied, but there is no general consensus on an effective dose or duration [27]. Many guidelines recommend the use of corticosteroids as no major study has shown long‐term efficacy. If they are used, a single injection or short duration should highly be emphasized due to severe side effects of chronic use including immunosuppression, metabolic disorders and GI bleeding.

Addition of an adjuvant medication should directly target a cause of pain (neuropathy, mus‐ cle spasm, etc.), and efficacy should be evaluated after initiation and periodically throughout. If a medication is found to not be efficacious, it should be removed or replaced. For additional information, clinicians can refer to neuropathic pain guidelines that provide evidence‐based recommendations for specific disease state‐induced neuropathic pain [29]. If acute or chronic pain is completely neuropathic in nature, the WHO's stepwise ladder is not appropriate to follow and a medication regimen targeting neuropathy should be initiated.
