Abstract
With worsening drug epidemics in the United States, proper pharmacological management in patients with chronic pelvic pain has very significant consequences. It includes chronic management of those patients as well as perioperative management. Multiple nonnarcotic medications have been shown to be very effective in managing patients with pelvic pain. The mainstay of treatment remains nonsteroidal anti-inflammatory medications. They are effective in any type of pain but particularly in dysmenorrhea and inflammatory pain. Anticonvulsants such as gabapentin have been shown to be effective in neuropathic type of pain as well as pre- and postoperative management. Many patients with pelvic pain develop significant pelvic floor muscle spasm. They do not appear to respond well to oral muscle relaxants but usually have very good responses to vaginal suppositories with various combinations of diazepam and other medications. In patients who do not respond to muscle relaxants botulinum toxin injections to pelvic floor muscles may provide muscle relaxation and therefore pain relief. Patients with pain related to nerves may respond to gabapentin and pregabalin but also benefit from use of lidocaine patches. Narcotics pain medications should be used very cautiously and as a last resort.
Editor’s Introduction
With worsening drug epidemics in the United States, proper pharmacological management in patients with chronic pelvic pain has very significant consequences. It includes chronic management of those patients as well as perioperative management. Multiple nonnarcotic medications have been shown to be very effective in managing patients with pelvic pain. The mainstay of treatment remains nonsteroidal anti-inflammatory medications. They are effective in any type of pain but particularly in dysmenorrhea and inflammatory pain. Anticonvulsants such as gabapentin have been shown to be effective in neuropathic type of pain as well as pre- and postoperative management. Many patients with pelvic pain develop significant pelvic floor muscle spasm. They do not appear to respond well to oral muscle relaxants but usually have very good responses to vaginal suppositories with various combinations of diazepam and other medications. In patients who do not respond to muscle relaxants botulinum toxin injections to pelvic floor muscles may provide muscle relaxation and therefore pain relief. Patients with pain related to nerves may respond to gabapentin and pregabalin but also benefit from use of lidocaine patches. Narcotics pain medications should be used very cautiously and as a last resort.
Introduction
Background
Significance
An understanding of the arsenal of pharmacological interventions available to the clinician and safety is essential for any provider caring for women with chronic pelvic pain. Most gynecological societal guidelines recommend an initial thorough evaluation and acknowledge that instituting empirical therapy is reasonable given there are often multiple identifiable and nonidentifiable contributing factors [1–3]. Many chronic pelvic pain disorders alter the nervous system, resulting in neuropathic pain. An appreciation of primary and adjuvant therapies becomes even more useful in advanced pain states.
Scope
This chapter reviews the literature and best clinical practices for pharmacological management of chronic pelvic pain of benign gynecological origin. There are several common causes of pain, especially nongynecological visceral pain, that are beyond the scope of these recommendations because of inherent differences in pathophysiology. Of note, interstitial cystitis/bladder pain syndrome, endometriosis, and dysmenorrhea are commonly encountered by the gynecologist but pharmacological management will not be comprehensively reviewed here, as there are several unique targeted therapies that are described in other disorder-specific chapters.
The highest level of evidence by synthesized data either through societal guidelines or qualitative systematic reviews and quantitative meta-analyses (e.g., Cochrane Database Systematic Reviews) were used in the preparation of this chapter. Medication and disorder specific reviews within the past 15 years were included to supplement consensus statements. The Royal College of Obstetrics and Gynaecologists (2012), European Association of Urology (2014), and American College of Obstetrics and Gynecology (2020) have recently published clinical guidelines on chronic pelvic pain [1, 3]. The Society of Obstetricians and Gynaecologists of Canada (SOGC) clinical guideline on chronic pelvic pain has not been updated since 2005 [1].
Limitations of the Evidence Base
Owing to the limitation of evidence-based treatments for pelvic pain, outcomes are inferred from neuropathic pain literature from other regional and global pain syndromes [4]. These disorders include peripheral diabetic neuropathy (DN), fibromyalgia, trigeminal neuralgia, postherpetic neuralgia (PHN), and postoperative pain. Most chronic pain patients are managed with multimodal regimens as recommended by the American Pain Society; however, data are sparse regarding the most effective combinations or if combination therapies are superior to monotherapy for specific conditions [4].
Approach to Chronic Pelvic Pain Management
General Strategies
A general understanding of best practices in chronic pain management is prudent before delving into specific therapeutics. Most published algorithms are based on trial-and-error and on clinical experience. Most societal guidelines recommend a multimodal approach to maximize benefit/risk ratio; some combinations may provide synergistic benefits. Overarching themes in management reviewed in this chapter include starting with medications with greatest chance of benefit, titrating up from a low starting dose to minimize risks.
Targeted Therapy
Many pharmacological treatments have focused on specific pathologies that are common and recognizable within the modern schema for gynecological chronic pelvic pain: leiomyomata, endometriosis, adenomyosis, external genitalia pain syndromes (e.g., vulvodynia), and pelvic floor musculoskeletal and neurological disorders. Chronic pelvic pain is often an impetus in development of neuropathic pain. The etiology of neuropathic pain can be a direct result of various factors; depending on the lesion location, this can originate centrally or peripherally. Clinically, patients with this type of pain can experience different phenotypes including reflex changes to hyperalgesia, paresthesia, and dysesthesia.
Adverse Side Effects
Pharmacological management of chronic pelvic pain is not without risk of harm [5]. Throughout each section within this chapter, a brief review will be provided of clinically significant and common adverse effects with a focus on data from pelvic pain randomized controlled trials (RCTs) when available. A review of pharmacological interactions is prudent before starting new medications, particularly for patients with polypharmacy. Many helpful web-based tools exist to this end (e.g., Lexicomp Interact online program).
Nonopioid Analgesics
Also called simple analgesics, nonopioid analgesics are among the most commonly used medications for pain in the general population owing to their easy access, low cost, generally well tolerated side effects, and suitability for long-term use. This class includes acetaminophen/paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs). They all have analgesic and antipyretic properties while the latter also provides antiinflammatory effects. Most gynecological literature regarding efficacy of NSAIDs has targeted dysmenorrhea given its bioplausibility as a direct inhibitor of that pain pathway or for postprocedural pain management. There are surprisingly few placebo-controlled RCTs specifically assessing the efficacy for other etiologies of pelvic pain. In fact, there were no studies identified for the treatment of chronic noncyclic pelvic pain. In a 2012 comparative effectiveness review sponsored by the Agency for Healthcare Research (AHRQ) the authors found the literature addressing therapies for CPP in women was of poor quality and too inconclusive to guide treatment decisions [5]. Similar to other conditions, the evidence for the use of this class is otherwise derived from expert consensus, inference from studies of other pain syndromes or pathways, and common sense.
Nonsteroidal Antiinflammatory Drugs Description
NSAIDs are primarily subdivided into nonselective cyclooxygenase (COX)-1 and COX-2 enzyme inhibitors and selective COX-2 enzyme inhibitors. All of the available NSAIDs differ in the degree of the binding affinity [6]. Prostaglandins are implicated in several pathways that explain both the analgesic efficacy and also the side effect profile for NSAIDs. Unlike COX-1, COX-2 is differentially expressed and increased with inflammatory states. Endometrial tissue levels of COX-2 products are highest during menses [6]. From these findings and other basic science and clinical studies, it is hypothesized that COX-2 is implicated predominantly within the cyclic pain pathway whereas COX-1 has been more responsible for adverse side effects, especially of the gastrointestinal (GI) and cardiovascular systems. At the time of this writing, celecoxib remains the only readily available nonselective COX-2 inhibitor and requires a prescription.
Preemptive NSAID dosing has been shown to reduce overall analgesic dose requirements in postoperative pain studies and shows promise from limited basic science evidence [7]. Nearly complete prostaglandin synthesis suppression can be induced with naproxen if given before the activation of COX-1 and COX-2 pathways. The effect is dramatically less with COX-2.
Efficacy
Supporting literature is robust showing NSAIDs as a highly effective medication for management of dysmenorrhea. In a landmark 1984 systematic review, 72% of women with primary dysmenorrhea reported significant pain relief with NSAIDs alone versus 15% by placebo effect and 18% with minimal to no response [6]. However, the use of NSAIDs as they related to primary dysmenorrhea treatment will not be reviewed in this part of the chapter.
There are few trials investigating NSAIDs for the treatment of other gynecological pain conditions such as endometriosis, leiomyomas, and adenomyosis. A 2014 Cochrane review of NSAIDs used for treatment of endometriosis pain revealed only one eligible, low quality trial (N = 24) [8]. The reported benefit was nonsignificant (odds ratio [OR] 3.27, 95% confidence interval [CI] 0.61–17.69). There have not been any more recent RCTs for this indication. Though evidence for NSAIDs in secondary dysmenorrhea is lacking, societal guidelines agree it is a reasonable first-line analgesic because of its accessibility, affordability, familiarity to patients, and tolerability[1, 3, 9]. There is insufficient evidence evaluating NSAID use for neuropathic pain to draw conclusions on efficacy.
Comparative Effectiveness
The available literature to assess differences between NSAIDs and acetaminophen/ paracetamol is limited to dysmenorrhea trials and generally of low quality. For the purpose of this chapter, the evidence will not be reviewed here.
Adverse Side Effects and Contraindications
The only statistically significantly increased risks of adverse effects with NSAIDs included GI (e.g., nausea and indigestion) and neurological (e.g., headache, drowsiness, dizziness, and dry mouth) symptoms [10]. Overall NSAIDs were 29% more likely than placebo to result in any adverse effect, with neurological symptoms being more strongly associated than GI symptoms, OR 2.74 (95% CI 1.66–4.53) versus OR 1.58 (95% CI 1.12–2.23), respectively. This difference was not reflected in short-term follow-up studies. Robust general medicine literature clearly establishes much more serious risks for long-term use, particularly regarding cardiovascular and bleeding risks. Naproxen has been the least cardiotoxic NSAID in some studies [11].
NSAIDs should not be used in patients with significant renal dysfunction, history of GI bleeding, significant cardiovascular conditions, liver cirrhosis, and aspirin-sensitive asthma. Cautious use should be considered in the elderly, who are more susceptible to complications due to comorbidities. NSAIDs are also not recommended in patients on anticoagulation therapy, particularly coumadin, due to increased bleeding risks.
Acetaminophen/Paracetamol
The mechanism of action remains unclear for acetaminophen/paracetamol. It is thought to act similarly to NSAIDs in inhibition of the COX enzyme but only within the central nervous system (CNS) and through a different mechanism. Its lack of peripheral activity explains why it has no antiinflammatory properties. There have been well designed trials demonstrating analgesic efficacy for postoperative pain and for reducing opioid use in the immediate postoperative period [7]. Some nociceptive pain conditions such as low back pain and arthritis have evidence of small benefits over placebo as well. However, there are no RCTs assessing its efficacy for neuropathic pain or chronic pelvic pain. As it is easily accessible, has few restrictions, and is well tolerated, it is a reasonable first-line therapy and is often used in combination with NSAIDs before attempting other therapies for pelvic pain [1–3]. The primary concern with regard to adverse effects is hepatic toxicity, with the upper limit of the recommended maximum dosing at 3–4 grams per day [11]. A lower maximum threshold of 2 grams per day may be warranted for older adults and if chronic daily therapy is instituted.
Opioids
Description
Opioids include the formal class of opiates, substances derived from opium including the archetypal analgesic morphine, and synthetic compounds that bind to opioid receptors nonselectively or selectively within the CNS and peripherally. There are three subclasses of opioid receptors (mu, kappa, and delta) that are most relevant to pain physiology, and varying affinities by different opioid medications determine many of their pharmacological properties such as analgesic potency and therapeutic index. Dosing for opioids should ideally be short term with clear expectations for indication and duration using the lowest possible dose, though some patients will inevitably require chronic and escalating use. Frequent reassessment within 1–4 weeks of initiating or dose changes is indicated regarding efficacy and adverse side effects monitoring. In addition to a clearly documented pain contract delineated for the provider and patient, routine surveillance is recommended through both state-based prescription drug monitoring program databases and also urinary toxicology testing to assess for personal abuse or diversion. There are many established guidelines for prescribing opioids for chronic noncancer pain available for more thorough review; the CDC guidelines were updated in 2016 [12].
Efficacy
In a 2006 meta-analysis by Furlan et al. for opioid use in chronic noncancer pain, there was a moderate positive effect size for pain control and small positive effect size for functional outcomes when compared with placebo. Notably the number of patients who withdrew from the trials due to inadequate pain control with opioids was half the rate of placebo (15% vs. 30). Altogether 80% of trials examined nociceptive pain (e.g., arthritis, back pain), with the remainder targeting neuropathic or mixed pain (e.g., fibromyalgia, postherpetic neuropathy). Follow-up was short term, with a mean duration of 5 weeks. Medications studied including tramadol, codeine, oxycodone, morphine, and propoxyphene/dextropropoxyphene. The latter pair are no longer recommended for use due to high risk of toxicities. In a subset of trials comparing weak opioids and nonopioid analgesics there was no difference in pain control outcomes and slight but significantly worse functional outcomes for opioid use. Strong opioids (e.g., oxycodone, morphine), however, had significantly better pain control than nonopioid analgesics [13].
The CDC recommends against use of long-acting opioids for acute pain but these may be indicated for chronic pain [12]. A systematic review of 34 RCTs in chronic noncancer pain concluded there was insufficient evidence of a superior long-acting opioid or if long-acting was superior to short-acting in terms of pain or rates of adverse events [11,12].
Adverse Side Effects
CDC has recommendations for maximum doses to avoid the risk of adverse effects due to risks of respiratory depression and overdose [12]. Additionally, patients may have differential tolerance between opioids; dose reductions of at least 50% should be used for conversions. Up to two-thirds of deaths from the use of DEA Schedule II drugs involve combined opioids and benzodiazepines and thus concomitant use is ill advised [14].
The risk of chronic use after exposure to opioids has been demonstrated in some studies but a systematic review was unable to adequately address this question because of heterogeneity in study design and results [11]. It is unknown whether there are any differences in risk of abuse between various opioids. Recent retrospective evidence from state and national database studies supports that 5% of opioid-naive patients prescribed opioids for chronic pain will convert to persistent users, though several covariates are strongly predictive including age (risk during reproductive age ranging 2.2%–6.5% when stratified by decade of life) [15]. Use of opioids beyond 90 days postoperatively after minor and major procedures has similarly been demonstrated as high as 5.9% and 6.5% respectively versus 0.4% among nonsurgical controls [16]. The study authors postulated that this use consisted primarily of treatment of nonsurgical chronic pain or neuropsychiatric comorbidities. Full elucidation of this relationship and indications for which opioids may be misused is greatly needed.
Risks of adverse side effects are much more common than addiction and diversion. In systematic reviews by Moore and McQuay in 2005 and Eisenberg et al. in 2006, only nausea; vomiting; constipation; and cognitive impairments such as drowsiness, dizziness, and somnolence were more common than with placebo, ranging 15%–33% [11]. Discontinuation rates due to side effects varied as well, from 11% to 22%. Major limitations of these effect estimates are also the short duration of follow-up and fixed dosing, which do not reflect clinical use in chronic pain disorders. There are several other well recognized but less common adverse effects including hypogonadotropic amenorrhea and impaired neuropsychological performance.
Opioids with Adjuvant Mechanisms
Tramadol is a mu-opioid receptor agonist with additional effects as a weak serotonin– norepinephrine reuptake inhibitor (SNRI). Tapentadol has a stronger opioid effect than tramadol and similar to that of hydrocodone, and it only inhibits norepinephrine reuptake. The nonopioid mechanism is thought to provide additional analgesia, similar to gains seen with traditional SNRIs and tricyclic antidepressants [11]. This benefit is largely theoretical. Only small improvements in pain control and small decrements in adverse events as compared with traditional opioids have been reported in literature. Though the risks of abuse with tramadol in a large randomized controlled trial of 11,352 patients with chronic noncancer pain were similar to those for nonopioid analgesics, there are psychoneurological risks to consider [11]. Both tramadol and tapentadol can increase the risk of seizures in patients with epilepsy, and tramadol can precipitate serotonin syndrome when combined with other serotonin reuptake inhibitors. Therefore one should specifically screen for contraindications including seizures and concomitant use of psychiatric and pain medications before prescribing either medication.
Conclusion
Though opioids have a notorious reputation, there may be a role for chronic noncancer pelvic pain when reserved for acute pain flares or for short-term use while pursuing alternative therapies. A subset of patients will eventually require chronic opioid use and should be managed by a healthcare provider skilled in special challenges within this population. A goal of using the full armamentarium of pharmacological management options should be to reduce the use of opioids, especially in the setting of a national epidemic of dependence and inappropriate use for both medical and nonmedical reasons.
Antiepileptics
For several decades antiepileptics, formerly called anticonvulsants, have been used to treat a number of neurological and psychiatric disorders such as neuropathic pain and depression. In the chronic pain literature, most evidence supports treatment when pain is characterized as “lancinating or burning” [11]. Archetypal indications include PHN, DN, and fibromyalgia. The “gabapentanoids” have been the most studied compounds within this class and have the best evidence of efficacy in chronic noncancer pain as well as pelvic pain.
Gabapentanoids
Description
This subclass of antiepileptics consists of the prototypical gabapentin and its successor pregabalin, which is more lipophilic and may have improved uptake across the blood–brain barrier. Both medications act primarily in the CNS by binding the alpha-2–delta-1 subunit of voltage-gated calcium channels within inhibitory neurons, thus antagonizing excitatory neurons [11]. The complex balance of accessory excitatory and inhibitory neurons modulating nociceptive and nonnociceptive sensory transmission is implicated in the theory of central sensitization and may explain why a subset of chronic pelvic pain patients benefit from treatment with these medications. In other words, gabapentanoids may either provide analgesia from direct inhibition of increased peripheral neuropathic pain or through modulation of a more complex central process.
Owing to a common incidence of side effects, we recommend starting at a low dose and titrate up as tolerated to provide adequate analgesia (see Table 6.1 in the Appendix). These medications have few long-term serious risks if monitored appropriately, which makes them ideal candidates for management of chronic pelvic pain. However, most patients will not find substantial benefit even after escalation to therapeutic dosing, so discontinuation should be considered after a trial of 3–6 months if no effect is observed. For patients who develop bothersome side effects, weaning to either a lower dose or transitioning to an alternative therapy if there is no longer any benefit should be considered.
Efficacy
The evidence supporting the use of gabapentanoids for pelvic pain relies heavily on nongynecological literature in neuropathic pain. In a 2012 systematic review of pharmacological management noncyclic/mixed noncyclic and cyclic pelvic pain, only one study (N = 56) was identified that compared gabapentin versus amitriptyline versus both [5]. After 2 years of follow-up, gabapentin alone (visual analog scale [VAS] pain score 1.9 ± 0.9) or in combination with amitriptyline (VAS pain score 2.3 ± 0.9) outperformed amitriptyline alone (VAS pain score 3.4 ± 0.9). There was no placebo-controlled group in that study, and at the time of this writing there is no other published evidence for efficacy of either gabapentin or amitriptyline specifically in chronic pelvic pain. A 2013 Cochrane review of antiepileptic pharmacotherapy for vulvodynia failed to identify any RCTs. While most studies reported some positive outcomes for improved pain or sexual function, there is a high rate of spontaneous resolution and fluctuation of symptoms in vulvodynia, and no studies compared the interventions with placebo [17].
Several Cochrane reviews over the past 20 years have analyzed the efficacy of antiepileptics for neuropathic pain and fibromyalgia, serving as indirect evidence used to support the use of this class in treatment of pelvic pain conditions. A 2013 Cochrane review summarized the findings of previous reports [18]. Number needed to treat (NNT) was calculated to achieve ≥50% reduction in pain for one patient. Both gabapentin and pregabalin were found to have good evidence supporting its use in diabetic neuropathy (gabapentin 600–3600 mg/day; NNT 5.8, 95% CI 4.3–9.0 and pregabalin 600 mg/day; NNT 6.3, 95% CI 4.6–10.0) and PHN (gabapentin 1800–3600 mg/day; NNT 7.5, 95% CI 5.2–14 and pregabalin 600 mg/day; NNT 4.0, 95% CI 3.1–5.5). Pregabalin was also found to be effective for central neuropathic pain (600 mg/day; NNT 5.6, 95% CI 3.5–14.0) and fibromyalgia (600 mg/day; NNT 11, 95% CI 7.1–21.0). The proportion of patients with ≥30% of pain relief is not as well correlated with clinically significant functional outcomes but nonetheless had more favorable NNTs. As gabapentin was the first of its class and had rapid uptake, becoming the most prescribed antiepileptic in the United States in less than 10 years after its initial FDA approval, there has been little incentive to conduct further studies on the majority of its use for off-label indications such as gynecological neuropathic pelvic pain [19].
Adverse Effects and Contraindications
A 2013 Cochrane review of antiepileptics for neuropathic pain summarized common adverse effects with a pooled estimate of 10% of patients discontinuing therapy for these reasons [18]. However, there was no difference in the rate of serious adverse events between gabapentanoids and placebo in RCTs, though with mostly short-term follow-up. The most common effects are neurological: somnolence, dizziness, blurry vision, and cognitive and motor impairment. Experiencing any adverse event was more common than with placebo, with both gabapentin ≥1200 mg/day (66% vs. 51%; OR 1.3, 95% CI 1.2–1.4) and pregabalin 600 mg/day (83% vs. 67%; OR 1.3, 95% CI 1.25–1.4)[18]. Rates of discontinuation due to adverse effects of pregabalin were demonstrated to have a dose–response relationship in that same Cochrane review, ranging from 7.1% for patients taking 150 mg/day to 22% for patients taking 600 mg/day compared to 6.2%–10% for placebo.
Other Antiepileptics
In a 2013 Cochrane Review of antiepileptics used for neuropathic pain and fibromyalgia, there was either inadequate or low-quality evidence for use of alternatives beyond gabapentinoid subtypes. A 2011 review specific for the management of gynecological neuropathic pain highlighted evidence against use of lamotrigine and supported topiramate as a reasonable alternative to gabapentin [20]. Side effect profiles are similar to those of gabapentanoids but rare serious events have been reported such as blood dyscrasias [18].
Antidepressants
Antidepressants have been used for the treatment of chronic pain for decades, predominantly with amitriptyline – one of the earliest synthesized tricyclic antidepressants. Other classes found in both the published literature and common use include SNRIs, and to a lesser extent, selective serotonin reuptake inhibitors (SSRIs). Dosing and monitoring guidelines for antidepressants used for the treatment of chronic pain are similar to those for gabapentanoids and are reviewed in greater detail in that section, as the body of high-quality evidence is more robust.
Tricyclic Antidepressants
Description
Though high-quality, double-blind placebo-controlled RCTs are lacking, decades of clinical experience with tricyclic antidepressants (TCAs) support the expert consensus recommendations for their use in chronic pelvic pain, particularly if neuropathic pain is within the indication for treatment. Most experts theorize that a significant benefit from TCAs is derived directly from their antidepressant effects, though these are mostly seen at higher doses than typically used for pain (>100 mg/day)[11]. However, studies investigating this relationship have failed to demonstrate a correlation between effects on mood and pain relief. Similarly, patients without depressive symptoms may still have improvement in pain scores [21]. TCAs act primarily by inhibition of the reuptake of serotonin and norepinephrine but have multiple sites of activity, including antihistamine and anticholinergic effects. While amitriptyline and nortriptyline are the best studied TCAs for this indication, others such as imipramine may be used as alternatives.
Efficacy
Studies supporting TCAs as effective medications for chronic noncancer pain have severe limitations, most notably that sample sizes were small and there was significant heterogeneity or simply lack of explanation of study design [11]. Two Cochrane reviews published in 2015 provided pooled analyses of efficacy from modernized studies of the two most commonly used TCAs: amitriptyline and nortriptyline[21, 22]. All of the 17 RCTs included for amitriptyline were no better than third-tier evidence. No data synthesis was performed because of a high risk of bias. There was no convincing benefit of amitriptyline versus active intervention shown for DN, mixed neuropathic pain, PHN, spinal cord injury, cancer-related pain, or HIV neuropathy. Only two small studies demonstrated amitriptyline improved pain over placebo and were specific to PHN. A limited analysis of the best available evidence from four studies for the first three indications suggests a significant benefit for amitriptyline over placebo (OR 2.0, 95% CI 1.5–2.8) with NNT 5.1, 95% CI 3.5–9.3, though likely overestimated [23]. This effect size is similar to that seen with gabapentanoids for the treatment of neuropathic pain. Few high-fidelity studies were available for nortriptyline reviewed, and all proved to be short term and third-tier evidence. Nortriptyline did not perform better than active intervention (e.g., amitriptyline, gabapentin) or placebo, where most studies reported approximately one-third of participants met the prespecified goal for pain relief or improved functional outcomes regardless of which therapy was used.
An examination of the literature supporting TCA use for vulvodynia provides an excellent case study in the limitations of the available data. In a 2013 systematic review of antidepressants used for the treatment of vulvodynia, there were only 2 RCTs identified among a total of 13 studies, and both involved TCAs: oral desipramine and oral amitriptyline. Despite retrospective and prospective observational data to support efficacy of TCAs for pain control and improved sexual function in vulvodynia, there were no differences between treatment and placebo in controlled trials [24]. Base on grade A evidence, the vulvodynia expert committee recommended against the use of TCA medication for management of provoked vulvodynia [25].
Adverse Effects and Contraindications
Secondary amine TCAs (e.g., nortriptyline, desipramine) are considered to have lower rates of side effects than tertiary amine TCAs (e.g., amitriptyline, imipramine), which may be due to differential affinity for neurotransmitter inhibition. Secondary amines are more selective for norepinephrine and have fewer anticholinergic side effects. The anticholinergic effects predominant with all TCAs include dry mouth, dizziness, sedation, constipation, and weight gain. In a Cochrane review of TCA use for the treatment of neuropathic pain, 55% of participants experienced at least one adverse event as compared with 36% from placebo [21]. Importantly, there was an increased risk of serious adverse effects with TCA use in that Cochrane review: 6.6% with amitriptyline versus 1.8% with placebo including one death while using amitriptyline. Special consideration should be taken when prescribing TCAs to any elderly patient or woman with cardiovascular disease [11]. Some experts recommend performing baseline cardiac risk assessment including EKG for patients with risk factors or for age greater than 40 years [20]. There are insufficient data to estimate the rate of side effects with nortriptyline specifically from studies of neuropathic pain but most report at least two-thirds of patients will experience at least one adverse effect.
Serotonin–Norepinephrine Reuptake Inhibitors
Description
Among the antidepressant class of serotonin and norepinephrine inhibitors, duloxetine and venlafaxine are the best well studied for treatment of neuropathic pain and fibromyalgia. They share the same primary mechanism of action as tricyclic antidepressants, but duloxetine in particular has received FDA approval for a breadth of neuropathic pain conditions likely due to a higher quality of research standardization. Venlafaxine has evidence from animal studies for minor opioid receptor agonist activity but, like duloxetine, acts predominantly by neurotransmitter reuptake inhibition. Similarly to TCAs, the SNRIs often exert their analgesic effects at lower doses than commonly required for their antidepressant effects [20].
Efficacy
Two Cochrane reviews in 2014 summarized available evidence for the use of duloxetine and venlafaxine for neuropathic pain and fibromyalgia. Duloxetine was investigated in 8 studies for use in diabetic neuropathy (N = 2728) and 6 studies for use in fibromyalgia (N = 2249)[26]. Notably, most studies were conducted by the manufacturer, which may explain why such a large number of participants were able to be recruited. Importantly, a clinically meaningful reduction in pain by ≥50% was assessed and decreased heterogeneity of the pooled analysis. High-quality evidence showed greater benefit for DN (NNT 5, 95% CI 4–7) than for fibromyalgia (NNT 8, 95% CI 4–21) or somatic pain symptoms related to depression (NNT 8, 95% CI 5–14). An effective dose of duloxetine to achieve significant reduction in pain was 60 mg/day, with a maximum dose of 120 mg lacking to show improved efficacy.
Only 6 of the 14 studies (total N = 460) identified for venlafaxine could be included in the Cochrane review [27]. Small sample sizes and short follow-up were primary deficiencies; no study reported on outcomes after greater than 8 weeks of treatment. Nonetheless, all studies reported positive outcomes. The largest RCT included 245 participants and demonstrated a significantly greater proportion of patients achieving ≥50% reduction in pain with venlafaxine (56% vs. 34% placebo, NNT 4.5).
Adverse Effects
SNRIs are generally better tolerated than TCAs because of their lack of nonselective effects. A 2017 Cochrane review of venlafaxine used for the treatment of neuropathic pain showed significantly greater rates of adverse effects with treatment but also high rates with placebo, 89% versus 75% respectively [26]. Other, non-placebo-controlled studies, reported rates as low as 44%. The most common side effect of SNRIs is nausea, which may be limited by titration from a low starting dose and taking the medication with food [11]. Other adverse effects include dizziness, somnolence, dry mouth, and sweating.
Selective Serotonin Reuptake Inhibitors
A 1997 systematic review failed to show any benefit of SSRIs for chronic pain management. Alternative therapies have been shown clearly superior in classic syndromes of neuropathic pain. Limited data support use in fibromyalgia, though other antidepressants – particularly TCAs – are likely more efficacious [11]. Nonetheless, 47% of patients treated with SSRIs in the review reported some degree of improvement in somatic symptoms, predominantly pain.
Muscle Relaxers
Description and Efficacy
Muscle relaxers include a heterogeneous group of medications that act primarily as antispasmodics. One review of pharmacotherapy for chronic noncancer pain subclassifies them by FDA-approved indication either for spasticity (e.g., baclofen, dantrolene, tizanidine) or musculoskeletal conditions (e.g., carisoprodol, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine)[11]. No studies demonstrated superiority among the class of muscle relaxers. Most evidence of efficacy in chronic noncancer pain is derived from use in fibromyalgia, which often has additional spasticity symptoms separate from central or neuropathic pain. A 2005 meta-analysis found 5 placebo-controlled RCTs for the treatment of fibromyalgia with cyclobenzaprine with a pooled OR 0.21 (95% CI 0.09–0.34) and NNT 4.8 (95% CI 3.0–11)[28]. A significant component of therapeutic benefit from muscle relaxers is likely from its sedative effects and improvement in sleep dysfunction, as evidenced in that same review. Pain and sleep had small improvements, and while there were small initial improvements in fatigue or tender points at 4 weeks, the benefit did not persist. This finding is consistent with the manufacturer prescribing guidance for short-term acute muscle spasm. Another possible mechanism for efficacy for cyclobenzaprine in particular is that its chemical structure is similar to that of tricyclic antidepressants. Accordingly, it carries risks of serotonin syndrome when combined with other psychoactive drugs. Tizanidine is a centrally acting alpha-2 receptor inhibitor, and in addition to sedation commonly seen with that class, it carries risks for hypotension because of its concomitant vasodilatory effect. A systematic review was unable to assess risks of abuse with muscle relaxers, which has been a concern because of the sedative effects. Most reports of abuse have involved carisoprodol, though baclofen is also associated with risks of withdrawal [11].
There are no high-quality RCTs assessing long-term outcomes. Patients with chronic pelvic pain who may benefit most from treatment would likely have concomitant myofascial pain involving the pelvic floor, abdomen, or lower back and significant sleep dysfunction. The evidence to support the use of muscle relaxers is limited; however, they might be beneficial as adjunctive multimodal therapy versus maintenance therapy.
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