A Look at Commonly Utilized Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) in Chronic Pain

Introduction

Chronic pain continues to be one of the leading healthcare cost burdens in the United States and affects roughly 30% of the US population.¹ It can be defined as ongoing pain lasting longer than six months. Furthermore, neuropathic pain is caused secondary to disease or a lesion of the somatosensory system, including peripheral fibers and central neurons.^2,3

Typical conditions that may result in neuropathic pain include diabetes mellitus, alcoholism, infection, and significant nervous system disorders such as stroke, Parkinson’s disease, and multiple sclerosis. Patients experiencing neuropathic pain report symptoms of shooting, burning, or stabbing pain and tingling, numbness, or a “pins and needles” sensations.

Generally, the treatment options for chronic and neuropathic pain include physical therapy, pain psychology, medical management, and interventional therapy, including surgical interventions. Various pain medications have been trialed with an increasing use of membrane stabilizers and antidepressants to treat neuropathic pain conditions. In recent years, antidepressants such as serotonin noradrenaline reuptake inhibitors (SNRIs) have been used to treat a wide range of pain conditions in addition to their use for depressive disorders but at lower doses for analgesia with analgesia a different risk profile and side effects at these doses.^4–6

SNRIs function by inhibiting serotonin and noradrenaline reuptake in the pre-synaptic cleft of the neuron, with numerous studies showing their potential use for the treatment of musculoskeletal pain, low back pain, and neuropathic pain conditions.^2,3,7 Serotonin and norepinephrine are primarily involved in the modulation of pain via descending pain pathways in the brain and spinal cord^2,7 The descending pathways release the neurotransmitters above, and when there is dysfunction of these pathways, these antinociceptive pathways are likely to be involved.³ When monoamine reuptake inhibition occurs, the activity of these descending inhibitory pathway are increased along with their antinociceptive effects.^3,8 Additionally, patients with chronic pain often develop concurrent depression as these pathways are intertwined, affecting both pain and mood.^3,9 Fortunately, treating pain and depression can often be combined with the use of SNRIs.⁸

SNRIs often have better tolerability than selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), making them an apt choice for pain reduction in those with chronic pain.^7,8 In addition, some studies have demonstrated that SSRIs have little efficacy in treating chronic pain when compared to placebo or tricyclic antidepressants, suggesting that norepinephrine uptake inhibition may play an essential role in the analgesic properties of SNRIs.^7,10–14 Another advantage to SNRIs over other membrane stabilizers is that this drug class is more specific and does not act on muscarinic or histamine receptors, thus circumventing potential side effects. Despite this, there are still side effects such as dry mouth, insomnia, constipation, and nausea with SNRIs and up to 8-14 weeks to find the optimal dose.³ The three most commonly utilized SNRIs to treat chronic and neuropathic pain are duloxetine, venlafaxine, and milnacipran. Below we discuss these specific SNRIs in more detail.

Duloxetine

Duloxetine is an SNRI commonly used to manage depression, generalized anxiety disorder, painful diabetic neuropathy, and chronic musculoskeletal pain conditions (osteoarthritis and low back pain).¹⁵ Duloxetine’s primary route of administration is orally due to its excellent oral availability with no effect if taken with food. Duloxetine is >90% bound to albumin, has an elimination half-life of 12 hours in adults, and is excreted mainly in the urine and with a minor amount in the feces.¹⁶ Metabolism occurs via the hepatic system via CYP1A2 and CYP2D6 forming inactive metabolites.¹⁶ Typical doses for chronic musculoskeletal and neuropathic pain are 30-60 mg once a day. Common side effects, which are similar for most SNRIs, include headache, drowsiness, insomnia, fatigue, nausea, weight loss, weakness, change in libido; serious, though rare, side effects include suicidality, hepatoxicity, serotonin syndrome, and hyponatremia.^17,18 A gradation effect with low dosages targeting serotonin and higher doses increasingly targeting norepinephrine with dose-independent effect on dopamine is also noted.¹⁹

The analgesic effects of duloxetine likely involve the descending noradrenergic inhibitory system.²⁰ When duloxetine was studied in rats with hindlimb paralysis via spinal nerve ligation (SNL), it was found that three daily injections of duloxetine attenuated the hyperalgesia caused by SNL, improved noxious stimulus-induced analgesia, and provided effective treatment.²⁰ Furthermore, the rats treated with duloxetine had higher noradrenaline levels in the dorsal spinal cord than the control group.²⁰ This effect was inhibited by intrathecal injections of alpha-2-adrenoreceptor antagonists, suggesting that analgesic effects of duloxetine, and other SNRIs, are dependent on the noradrenergic descending inhibitory system.^20,21 Though duloxetine provides antidepressant effects, the pain relief is mainly due to directly targeting pain modulation.²²

Duloxetine can be used as a medication to treat one of the most common joint disorders in the USA, osteoarthritis.³ Patients suffering from chronic knee osteoarthritis were administered a 60 mg/day dose. They demonstrated sustained improvement in their pain for up to 48 weeks in addition to improvement in overall physical, mental, and emotional health.²³ When combined with pregabalin, duloxetine had mild improvement in patients with hand osteoarthritis.²⁴ At doses of 60 mg/day, duloxetine was also effective for treating pain in patients suffering from chronic low back pain (CLBP) irrespective of age or sex.²⁵ Oddly, patients who experienced early side effects of duloxetine (nausea, constipation, and drowsiness) appeared to have a more significant reduction in pain as those who did not, suggesting that adherence despite early side effects can result in increased improvement in pain.²⁵

Duloxetine can also be used to treat peripheral diabetic neuropathy (PDN). A randomized, double-blind placebo-controlled trial comparing duloxetine to placebo in patients with diabetic peripheral neuropathy revealed a statistically significant pain improvement (p < 0.001) on the 24-hour pain score compared to the placebo group.¹¹ Patients in the study were treated with duloxetine 60 mg once daily, duloxetine 60 mg twice daily, or placebo, and their 24-hour pain severity was measured on an 11-point Likert scale.¹¹ Another study found a similar reduction in the 24-hour pain score in patients with diabetic neuropathy treated with duloxetine compared to placebo but found no significant difference in duloxetine 60 mg once daily versus 60 mg twice daily.²¹ These studies revealed that duloxetine is both effective and safe in the management of neuropathies.^11,20,21

The use of duloxetine is not limited to osteoarthritis, CLBP, and PDN but can be used in other neuropathies. One randomized, double-blind placebo-controlled trial evaluated duloxetine on taxane-induced sensory neuropathy in breast cancer patients revealing duloxetine’s ability to provide effective neuropathic pain relief.²⁶ Moreover, duloxetine effectively decreased neuropathic pain and motor neuropathy in chemotherapy-related pain.²⁷ Cancer patients with chemotherapy-induced peripheral therapy were given a placebo, venlafaxine, or duloxetine. Their cranial, sensory, motor neuropathies, and neuropathic pain level were evaluated on day one, week 2, and week four after enrollment.²⁷ The study found that the level of cranial, motor, sensory, and neuropathic pain was significantly decreased in the venlafaxine and duloxetine groups compared to placebo, with the pain reduction being more significant in the duloxetine group compared to the venlafaxine group.²⁷ Another randomized, double-blind placebo-controlled trial was conducted on 70 patients experiencing neuropathic pain secondary to cancer refractory to opioid and gabapentinoid treatment.²⁸ Seventy patients with a Brief Pain Inventory - Short Form (BPI-SF) of 4 or higher were included to participate in the study to receive placebo or duloxetine treatment.²⁸ Domains such as continuous pain, intermittent pain, neuropathic pain, and effective descriptors were studied, and results revealed that neuropathic pain showed significant change in pain scores in the duloxetine group from day 0 to 10.²⁸

Fibromyalgia is a somatic disorder that typically results in widespread musculoskeletal pain. Typically, patients experiencing fibromyalgia report myalgias, arthralgias, fatigue, and sleep disturbances.²⁹ In general, patients suffering from fibromyalgia have a decreased quality of life and high levels of disability. Treatment for fibromyalgia symptoms consists of physical therapy, analgesic medications such as non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, or nerve pain medications. In recent years, the use of SNRIs such as duloxetine in the treatment of fibromyalgia pain has been studied. A randomized, double-blind, placebo-controlled trial of 393 patients received duloxetine or placebo treatment.³⁰ The primary assessment consisted of changes in pain scores, with secondary examinations consisting of quality of life improvement and safety outcomes.³⁰ The efficacy of duloxetine in controlling pain from fibromyalgia was limited, with no significant changes in pain scores reported 14 weeks post-treatment.³⁰ Despite no improvement in pain scores, secondary outcome measures such as quality of life and safety outcomes showed significant findings in the duloxetine group. It demonstrated that they might have potential use in the overall symptomatic improvement in patients receiving duloxetine.³⁰ Overall, compared to duloxetine in neuropathic pain, the use of SNRIs for fibromyalgia pain must be further studied. Although specific studies have shown improvement in secondary outcomes in patients experiencing fibromyalgia pain, the direct correlation between SNRIs and pain relief in chronic pain fibromyalgia patients is yet to be found. Other studies on the use of duloxetine for fibromyalgia have found that only a minority of patients experienced pain relief, and many patients experienced side effects that outweighed the benefits of treatment.³¹

Venlafaxine

Venlafaxine is another SNRI commonly used in the treatment of neuropathic pain. Similar to duloxetine, the route of administration is oral with typical doses ranging from 75-225 mg with a lower protein binding (27%), half-life elimination of 5 hours, hepatic metabolism via CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV), and excretion mainly through the urine.^32–34 The side effect profile is similar to duloxetine.

A 2017 systematic review assessed the use of venlafaxine to treat neuropathic pain.³⁵ The review concluded that venlafaxine was well-tolerated and demonstrated significant pain relief for neuropathic pain compared to placebo.³⁵ However, venlafaxine was nonsuperior to other medications used for neuropathic pain.³⁵ Another review found similar results among 11 randomized clinical trials, citing the tolerability of venlafaxine with limited adverse effects.³⁶

A double-blind placebo-controlled trial assessed the effects of venlafaxine extended-release on patients with diabetic neuropathy.³⁷ The study measured scores on the 100-mm Visual Analog Pain Intensity (VAS-PI) and the Pain Relief (VAS-PR) scales. For six weeks, patients were given a placebo, venlafaxine 75 mg, or venlafaxine 150-225mg.³⁷ They found that the pain VAS-PI scores decreased by 27% in the placebo group, 32% in the 75 mg group, and 50% in the 150-225 mg group.³⁷ Moreover, patients in the venlafaxine 150-225 mg group had statistically significant greater mean VAS-PR scores when compared to other groups.³⁷ The results suggest that a venlafaxine is an effective option for diabetic neuropathy.³⁷

Milnacipran

Milnacipran is an SNRI used to treat fibromyalgia and occasional off-label use to treat depression.³⁸ It effectively improves pain, fatigue, and function in patients with fibromyalgia.³⁹ Similar to duloxetine and venlafaxine, its route of administration is oral with typical doses ranging from 12.5-100 mg with a lower protein binding (13%), half-life elimination of 6-8 hours, and hepatic metabolism to inactive metabolites with excretion via the urine.³⁹ Milnacipran shares a similar side effect profile to the previous two SNRIs. It does, however, have a more significant effect on noradrenaline than serotonin compared to other SNRIs such as duloxetine, venlafaxine, and desvenlafaxine.⁴⁰

A 2012 Cochrane review examined the use of milnacipran for fibromyalgia and neuropathic pain and found that milnacipran was associated with decreased pain but an increased incidence of side effects.⁴¹ A meta-analysis of 19 studies involving 6,152 patients compared the efficacy of amitriptyline, duloxetine, and milnacipran to treat chronic pain.⁴² Amitriptyline was more productive than duloxetine and milnacipran in reducing pain, sleep disturbances, and fatigue.⁴² When compared to duloxetine, milnacipran was less effective in reducing pain but was superior in reducing fatigue in patients with fibromyalgia.⁴²

A double-blind, placebo-controlled clinical trial comparing 100 mg of milnacipran to placebo for one month found no significant difference between milnacipran and placebo in conditioned pain modulation, allodynia, or global pain thresholds.⁴³ However, another study examined the effects of milnacipran on pressure-evoked pain and cerebral processing of pain in patients with fibromyalgia and found that patients taking milnacipran had increased cerebral activity in areas of the brain associated with pain inhibition, including the caudate nucleus, anterior insula, and the amygdala.⁴⁴ Unfortunately, there was no statistically significant decrease in pain sensitivity in patients taking milnacipran compared to the placebo.⁴⁴

Conclusion

Chronic pain can be difficult to treat in patients and may be resistant to various medications and interventional options. Antidepressants and SNRIs offer a valuable therapeutic option for patients suffering from different neuropathic and chronic pain conditions. Duloxetine, venlafaxine, and milnacipran appear to have analgesic and some anti-inflammatory capabilities independent of their mood-stabilizing abilities. Additionally, these medications can be used at much lower dosages for their antinociceptive effects and have different side effects and safety profiles when used at these dosages. These medications may also provide opioid-free alternative pharmacologic options for patients struggling with debilitating pain, which is essential given the ongoing opioid crisis.^45–47 Further studies are still needed to establish better safety profiles and efficacy of antidepressant use in chronic pain. However, this article describes the safety and potential utility of SNRIs to treat a variety of chronic pain conditions.