Skeletal Muscle Relaxants, Antidepressants, Antiepileptics, Gabapentinoids

Anand M. Prem

Maryam Jowza

Dominika James

Introduction

While the prevalence of chronic pain in the adult population averages about 20% in the United States, the prevalence of acute pain is poorly understood. Thirty to fifty percent of patients in the hospital setting report pain of moderate to severe intensity. Over the past 20 years, the United States has seen a dramatic increase in deaths from opioid overdose that coincided with increases in the prescribing of opioids for pain management.¹ The escalation of overdose deaths from illicit opioids (including heroin and synthetic opioids such as fentanyl) seen in the past decade was driven in part by a growing number of people whose use began with prescription opioids.¹ According to the National Center for Drug Abuse Statistics, in 2017, more than 11 million Americans misused prescription opioids with 19 000 deaths involving prescription opioids in 2016 alone.

The liberal use of opioids in pain management was brought on by a combination of factors beyond the scope of this chapter, but central to the opioid crisis was the belief that addiction is rare as long as opioids were used to treat pain.¹ Recent studies however have shown that even a relatively brief exposure to opioids can increase the risk for chronic opioid use, opioid use disorder, and addiction. In many of these opioid-related overdose deaths, the initial exposure to opioids started with an opioid prescription for the management of acute pain, either in the immediate postoperative period or in the outpatient setting.¹ To address the ongoing opioid crisis, while adequate pain control is still a priority, every effort must be made to minimize opioid use in the perioperative period and increase the use of multimodal pain regimens. Enhanced recovery after surgery protocols focus on regimens that include nerve blocks, nonsteroidals, muscle relaxants, gabapentinoids, lidocaine, acetaminophen, and ketamine to decrease postoperative opioid consumption and reduce hospital stays. This chapter reviews the role of other nonopioid adjuvants such as antidepressants, muscle relaxants, antiepileptics as well as gabapentinoids as a component of a multimodal regimen for the treatment of acute pain (Table 36.1).

Antidepressants

The need to find safer, nonopioid agents to control pain is getting renewed attention, and antidepressants can play a significant role in pain treatment, improving the pain experience and reducing the need for opioids. Although antidepressants have ample evidence to support their efficacy in chronic pain over the past 50 years, they are often underutilized in the management of acute and postoperative pain.²

TABLE 36.1 NONOPIOID ADJUNCTS USED IN PAIN MANAGEMENT

Class	Mechanism of Action	Common Pain Indication	Notes
Skeletal muscle relaxants	Variety of agents with heterogeneous mechanisms of action on CNS	Limited evidence in support of use in acute back pain	Most agents have sedating side effects
Antidepressants	Of the various classes, TCAs and SNRIs most effective for pain; thought to strengthen descending inhibitory pain pathways at level of the spinal cord	Used most commonly in neuropathic pain states, fibromyalgia	Treatment of pain does not depend on treatment of mood
Antiepileptics	Heterogeneous compounds with various mechanisms of action, many agents act as inhibitors of voltage-gated Na channels	Neuropathic pain	More studies are needed to determine effectiveness in acute pain
Gabapentinoids	Inhibits the α2 delta subunit of the presynaptic voltage-gated calcium channels	Neuropathic pain	May have opioidsparing effect in acute pain
CNS, central nervous system; TCA, tricyclic antidepressant; SNRI, selective norepinephrine serotonin reuptake inhibitor.

The antidepressant classes used in pain include the following (Table 36.2):

Tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, maprotiline
Serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs): duloxetine, venlafaxine, milnacipran
Selective serotonin reuptake inhibitors (SSRIs): fluoxetine, paroxetine, citalopram, sertraline
Dopamine noradrenaline reuptake inhibitors: bupropion

Tricyclic antidepressants are antagonists of peripheral sodium channels and spinal N-methyl-D-aspartate (NMDA) receptors, which helps prevent central sensitization, a crucial component in the pathophysiology of acute postoperative pain.³ Although supported by a large body of evidence, the use of older TCAs in the management of pain is restricted by their numerous undesirable side effects.²,⁴ The SSRIs though have a better safety profile with fewer serotonin receptor-mediated side effects, but their use in pain has not been studied as extensively as they are less effective than traditional TCAs.² The newer class of serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors such as venlafaxine inhibit the reuptake of both 5-HT and NE, similar to the TCAs but without affecting other nontherapeutic receptors, leading to fewer side effects and better patient tolerance.² They also minimally interact with the cytochrome P-450 system leading to minimal interaction with other drugs making them a useful component of any multimodal pain treatment regimen.

Evidence for Antidepressants in the Treatment of Acute Pain

In a 2014 review of 15 studies involving 985 participants with acute postoperative pain who were treated with antidepressants, 8 trials demonstrated superiority to placebo for early reduction of pain.⁴ However, methodological concerns in these studies led the authors to conclude that there was insufficient evidence supporting the use of antidepressants in the treatment of acute pain as well as prevention of chronic postoperative pain. Future trials conducted in
carefully selected patients should evaluate the indications and contraindications for antidepressants in the acute perioperative setting as well as the potential for adverse drug interactions and increased risk for perioperative bleeding.⁴ Targeting patients particularly at high risk for developing chronic postsurgical pain may justify the risk of adverse effects from antidepressant use.⁴

TABLE 36.2 SUMMARY OF ANTIDEPRESSANTS

Class	Examples	Mechanism	Side Effects	Notes
Tricyclic antidepressants (TCAs)	Amitriptyline Nortriptyline Desipramine	Serotonin reuptake inhibition, norepinephrine reuptake inhibition, peripheral sodium channel antagonist, spinal N-methyl-D-aspartate (NMDA) receptor antagonist, anticholinergic, antihistaminic	Anticholinergic: xerostomia, tachycardia, urinary retention, constipation, amblyopia, and memory disturbances. Antihistaminic: sedation, drowsiness, weight gain. QT prolongation	Use limited by side effects
Selective serotonin receptor reuptake inhibitors (SSRIs)	Fluoxetine Paroxetine Citalopram Sertraline	Presynaptic serotonin reuptake blocker increases concentration of serotonin in the synaptic cleft	Nausea, diarrhea, tremor, headache, sedation, sexual side effects	Little analgesics efficacy
Selective norepinephrine serotonin reuptake inhibitors (SNRIs)	Duloxetine Venlafaxine Milnacipran	Serotonin (5-HT) and norepinephrine (NE) reuptake inhibition	Nausea, diarrhea, fatigue, somnolence, sexual dysfunction, hypertension	Well tolerated in neuropathic pain, fibromyalgia
Dopamine noradrenaline reuptake inhibitors	Bupropion	Noradrenergic and dopaminergic reuptake inhibition	Insomnia, nervousness, headache, irritability, lowered seizure threshold	Evidence for analgesic efficacy is mixed

As the analgesic effects of antidepressant drugs in chronic pain are typically seen days to weeks after initiation of treatment and escalation of doses, antidepressants may need to be initiated and titrated for days to weeks before surgery to optimize results in postoperative pain. In the absence of a clear time frame during which acute postoperative pain transitions to chronic postsurgical pain, antidepressants may need to be continued for several days or even weeks after postsurgical hospital discharge.⁴

Initiation of Treatment

Antidepressants typically need to be initiated at ¼ to ½, the recommended dose and titrated up gradually over 2-3 weeks to the full dose, to minimize side effects and improve patient tolerance. This is especially key in the elderly population. Pain patients are often on other medications that can potentiate the side effects of antidepressants, and this must be taken to account while titrating the dose. Frequent reassessments every 2-4 weeks is ideal before dose increases.

Mechanism of Action of Antidepressants as Analgesics

While there is consensus regarding the therapeutic benefits of antidepressants such as amitriptyline and duloxetine in the treatment of neuropathic pain, the mechanism by which they exert these actions is still poorly understood.²,³,⁴

Antidepressants in chronic pain act via several different postulated mechanisms. Reinforcement of the descending inhibitory pain pathways by increasing the amount of norepinephrine and serotonin in the synaptic cleft at both the supraspinal and spinal levels is one of the major mechanisms. Relief of underlying depression that adversely alters the affective component of pain is another. In acute pain, the primary mechanisms by which antidepressants act include blockage of sodium channels, NMDA receptor antagonism,³,⁴ blockade of central substance P receptors, and neuromodulation of the endogenous opioid systems.²

Within each class of antidepressant, there are again considerable differences in the extent of pain relief each drug provides in different populations. This was evident in one cross over study that looked at 31 patients with postherpetic neuralgia treated with amitriptyline and nortriptyline. While five patients had good pain relief with amitriptyline, they continued to experience moderate to severe pain with nortriptyline, and four other patients had good pain relief with nortriptyline but none with amitriptyline.

Painful Conditions That Respond to Antidepressants

While a variety of pain syndromes have been treated with antidepressants, neuropathic pain appears to be the most responsive to this class of drugs. Peripheral neuropathy from compressive, diabetic, postherpetic or HIV-related etiology, postradiation or chemotherapy neuritis, deafferentation pain, central pain syndromes, plexopathies, and postlaminectomy pain syndrome respond well to antidepressants,²,³,⁵ while their role in purely nociceptive pain is less impressive.

Tricyclic Antidepressants

This oldest class of antidepressants have the most evidence for their efficacy in the treatment of acute neuropathic and chronic pain. Their analgesic properties are independent of their antidepressant actions.²,³ However, they also act on multiple other neuroreceptors, which account for their numerous side effects, often limiting their use in the chronic pain patient.² The choice of a TCA to treat depression is primarily based on the patient’s tolerance of their anticholinergic and antihistaminic side effects, as they are all equally effective as antidepressants. Amitriptyline and imipramine are associated with more sedation, orthostatic hypotension, and weight gain. Nortriptyline has fewer anticholinergic side effects, and desipramine is the least of all TCAs.⁴

Role in the treatment of pain

TCAs have independent analgesic effects unrelated to their antidepressant effect, unlike SSRIs.²,³ They are superior to SNRIs as analgesics likely due to NMDA receptor antagonism and sodium channel blockade, in addition to their serotonin and norepinephrine reuptake inhibition.²,³,⁴ They are effective in pain from diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, radicular pain, poststroke pain, and chronic headaches.⁵ They have opioid-sparing properties and can be used effectively as preemptive analgesics in the management of acute perioperative pain. The usual analgesic doses (25-75 mg) are lower than the typical antidepressant dose (75-150 mg).⁵,⁶

Adverse effects

TCAs block the muscarinic receptors producing anticholinergic effects such as xerostomia, tachycardia, urinary retention, constipation, amblyopia, and memory disturbances. Sedation, drowsiness, weight gain, and potentiation of other central nervous system (CNS) depressants are attributed to histamine (H1) receptor blockade.³,⁴,⁵,⁶ They block Alpha 1 adrenergic receptors leading to drowsiness and postural hypotension, while Alpha 2 adrenergic receptor blockade can cause priapism and interfere with the antihypertensive properties of Alpha 2 agonists such as clonidine and methyldopa, if given simultaneously. Some TCAs block dopaminergic receptors causing extrapyramidal symptoms, rigidity, tremor, akinesia, tardive dyskinesia, neuroleptic
malignant syndrome, as well as increased prolactin production. All TCAs decrease the seizure threshold.

Initiation of treatment

Routine laboratory screening of blood urea nitrogen, creatinine, electrolytes, and liver function tests is recommended before starting treatment with TCAs. As they are arrhythmogenic and can prolong the QT interval, all patients above 40 years of age or with preexisting cardiac disease should get a baseline EKG to ensure that the corrected QT (QTC) interval is <450 ms. TCAs should be initiated at the lowest dose possible, especially in the elderly and gradually titrated up to therapeutic doses based on tolerance to side effects.

Discontinuation of TCAs: Abrupt discontinuation can lead to a withdrawal syndrome manifested by fever, sweating, headache, dizziness, nausea, and akathisia.

Overdose with TCAs: Unlike with SSRIs, overdose with TCAs can be lethal, and this is a leading cause of drug overdose deaths, usually a result of the anticholinergic and arrhythmogenic effects. TCAs have a narrow therapeutic range, requiring periodic blood level monitoring, as 3-5 times the therapeutic dose can be potentially lethal.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressants due to their efficacy and low side effect profile. They block the presynaptic serotonin reuptake pump in the CNS increasing the concentration of serotonin in the synaptic cleft and facilitating neurotransmission.

Role in pain treatment

There is little evidence to support SSRIs as sole analgesics.⁴,⁵,⁶,⁷ In conjunction with other analgesics in the patient with depression, pain reduction is seen due to improvement in the affective component of pain from its antidepressant properties. Case reports of sustained pain relief in patients with diabetic neuropathy are not supported by double-blind placebo-controlled trials.

Initiation of therapy

Prior to initiating therapy with SSRIs, no additional lab work is required. A thorough review of the patient’s medical history and concurrent medications will determine suitability. Titration of dose is based on clinical response and tolerance of side effects. Typically started at ½ the recommended dose and titrated up over the course of a week.

Paroxetine is more sedating and a stronger anxiolytic due to its anticholinergic effects and given at night. It has a shorter half-life than other SSRIs, with potential for withdrawal symptoms, if discontinued abruptly. Fluoxetine is more stimulating and given in the morning. Sertraline and citalopram are less sedating and usually prescribed in the mornings.

SSRIs induce or inhibit various cytochrome P-450 (CYP450) enzymes, increasing the serum levels of TCAs and benzodiazepines. They can also alter the levels of other drugs metabolized by the liver such as antipsychotics, lithium, carbamazepine, and analgesics methadone, oxycodone, and fentanyl. Paroxetine, fluoxetine, fluvoxamine to a lesser extent, and sertraline at higher doses inhibit cytochrome C2D6 increasing the blood levels of some opioid metabolites. Citalopram and escitalopram have minimal CYP450 enzyme inhibition.

Adverse effects

Nausea, diarrhea, tremor, headache, sedation, and overstimulation are common side effects. Sexual side effects like impotence, ejaculatory dysfunction, decreased libido, and inability to attain orgasm are seen in about 75% patients on SSRIs, especially with advanced age.⁸

Rarer side effects include akathisia, dystonia, syndrome of inappropriate antidiuretic hormone, and palpitations.³,⁴,⁵,⁶,⁷ Osteoporosis and increased risk for bleeding have been reported
with all SSRIs. Other medications the patient is on such as anticoagulants, antiplatelet agents and non-steroidal anti-inflammatory drugs (NSAIDs) can increase this risk, particularly in the high-risk population.

Serotonin syndrome is a significant risk when SSRIs are coadministered with SNRIs, TCA, triptans, monoamine oxidase inhibitors (MAOIs), antiemetics as well as several common analgesics such as tramadol, fentanyl, meperidine, and pentazocine. Use with tramadol can also lower seizure threshold. Overdosing on SSRIs is rarely fatal. Discontinuing SSRIs must include a gradual taper to avoid withdrawal symptoms such as nausea, diarrhea, headache, or myalgias.

Serotonin and Norepinephrine Reuptake Inhibitors

This class of antidepressants are increasingly being recognized as useful adjuvants in the treatment of musculoskeletal pain, fibromyalgia, and chronic pain.⁹ They bind to both the Serotonin (5-HT) and Norepinephrine (NE) transporters inhibiting their reuptake. They however differ in their affinity to these receptors and consequently their potency. They are also weak inhibitors of alpha-1, cholinergic and histamine receptors, accounting for their better side effect profile in comparison to TCAs. Unlike SSRIs, they typically have an ascending doseresponse curve leading to increased effect with higher doses.¹⁰ When used in conjunction with MAOIs or tramadol, these medications can cause serotonin syndrome.

Venlafaxine (brand name: Effexor)

Pharmacokinetics: Venlafaxine is a relatively weak 5-HT and an even weaker NE uptake inhibitor with an almost 30-fold difference in binding of the two transporters.¹⁰ At lower doses, it primarily binds to the serotonin transporter and as the dose is increased, it increasingly binds to the NE transporter. Venlafaxine is primarily metabolized by the cytochrome P2D6 (CYP2D6) enzyme to the active metabolite O-desmethylvenlafaxine (desvenlafaxine).¹⁰ Venlafaxine has a half-life of 5 hours, while desvenlafaxine has a half-life of 12 hours. This is further prolonged in patients with renal and hepatic impairment, requiring dose reduction by 50% in the presence of significant hepatic and renal dysfunction.¹⁰ Both have low protein binding and minimally interact with the cytochrome P450 system minimizing any potential for drug-drug interactions.

Initiation of treatment

Start low at 37.5 mg 2-3 times a day for a week and then titrate up to 150-225 mg/day based on clinical response and tolerance of side effects. Extra caution is required in hypertensive patients due to elevation of blood pressure at higher doses.

Adverse effects

Typical side effects include nausea, diarrhea, fatigue, somnolence, and sexual dysfunction, while higher doses produce mild increases in blood pressure, tachycardia, tremors, diaphoresis, and anxiety. Due to the inhibition of NE reuptake, dose-dependent elevation in blood pressure can occur, though rarely seen at doses below 225 mg/day.

Evidence for role in pain

Venlafaxine is structurally like tramadol and in mice has been shown to provide opioid receptor-mediated analgesia reversed by naloxone. Medical literature supports the use of venlafaxine in multiple pain states including fibromyalgia, headaches, and neuropathic pain conditions such as peripheral neuropathy, postherpetic neuralgia, intercostal neuralgia, complex regional pain syndrome, post-stroke pain, and atypical facial pain in multiple sclerosis.⁵,⁶,⁷,⁸,⁹,¹⁰ Its antinociceptive effect is independent of its antidepressant activity. Tolerance by patients is significantly better than with TCAs or SSRIs with minimal reported adverse events. Venlafaxine retains its efficacy with long-term maintenance therapy, unlike prolonged therapy with SSRIs.

Duloxetine (brand name: Cymbalta)

Duloxetine is a more potent 5-HT and NE reuptake inhibitor than venlafaxine. Duloxetine’s binding affinity is about 10:1 for the 5-HT and NE transporter. It is also a moderate inhibitor of CYP2D6, requiring caution when administered with other drugs that are preferentially metabolized by CYP2D6. This may require dose reductions as well as careful monitoring for adverse effects.¹⁰

Adverse effects

Nausea, dry mouth, constipation, insomnia, dizziness, asthenia, and hypertension are common side effects.⁵,¹⁰

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