Non-opioid pharmacologic treatment of chronic spinal cord injury-related pain

Abstract

Purpose: Spinal cord injury-related pain is often a severe debilitating condition that adversely affects the patient’s physical health, psychological wellbeing and quality of life. Opioid medications have historically been prescribed to this population with great frequency. As opioid abuse disorder becomes an ever-worsening public health issue, more attention must be placed upon non-opioid options. This paper reviews non-opioid medications to be considered when treating spinal cord injury-related pain. The pertinent literature is reviewed, and the advantages and pitfalls of various medication options are discussed in the complicated context of the individual with a spinal cord injury.

Methods: Peer-reviewed journal articles and medication package insert data are reviewed.

Results:. The non-opioid medications with the greatest evidence for efficacy in the treatment of chronic spinal cord injury-related pain are drawn from the antiepileptic drug and antidepressant categories though the specific selection must be nuanced to the particular individual patient. More research is required to understand the role of calcitonin, lithium, and marijuana in treating spinal cord injury-related pain.

Conclusions: The complex clinical situation of each individual patient must be weighed against the risks and benefits of each medication, as reviewed in this paper, to determine the ideal treatment strategy for chronic spinal cord injury-related pain.

Introduction

Chronic pain is a common sequela of spinal cord injury (SCI) though exact statistics vary widely depending on study techniques and outcome measures.^1–4 The pain is frequently difficult to quantify and categorize but has been associated with decreased function⁵ and increased rates of depression,^6–8 perhaps even more so than the severity of the injury itself.⁹

Many attempts at classifying spinal cord injury-related pain have been attempted. Twenty-nine systems of classification were catalogued by Hicken et al., in 2002^10–12 The Spinal Cord Injury Pain Task Force of the International Association of the Study of Pain (SCIP-IASP)¹³ proposed a new pain classification based on previous work by Cardenas¹⁴ and Bryce-Ragnarsson.¹⁵ The SCIP-IASP classification divides SCI related pain into four first tier types followed by tier 2 and 3 sub-groups. The first tier separates pain types into nociceptive pain, neuropathic pain, other pain and unknown pain.¹³

Pain after SCI is often difficult to differentiate from spasticity. Patients may use the term “spasm” when referring to a pain sensation and report pain when intending to report spasticity. It is important to be aware of this consideration when a patient's pain complaint does not respond to treatment as expected.

Opioid analgesics have been commonly used to treat SCI related pain.^16,17 With the current epidemic of opioid-related deaths, increased regulatory scrutiny has been given to opioid utilization amongst all non-cancer pain patients, and there is heightened awareness of the complications of opioid use, such as opioid use disorder.¹⁸ Individuals with SCI are not immune to the adverse reactions of opioids and have been found to have rates of abuse similar to those of their peers in the general population.¹⁹ There are limited options, however, with which to treat SCI pain and affected individuals often present with challenging comorbidities unique to the SCI diagnosis that must be considered. This paper offers a review of non-opioid non-invasive pharmacologic treatment strategies for SCI related pain in the context of the distinct needs of this population. See Table 1. It will focus primarily upon the treatment of SCI related neuropathic pain which is the most unique to spinal cord injury, the most studied of the SCI related pain types, and the most difficult to treat.

Table 1. Non-opioid non-invasive pharmacologic treatment strategies for SCI related pain.

Medication	Level of evidence of efficacy?73	CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord 50	Clinical Pearls
Capsaicin			May not be appropriate for patients that would have difficulty applying it safely or those susceptible to autonomic dysreflexia.
Pregabalin	Level 1	1st line treatment	FDA approved for SCI related neuropathic pain. May potentiate opioid medications and be a substance of abuse.
Gabapentin	Level 1	1st line treatment	Comparable efficacy to pregabalin. May potentiate opioid medications and be a substance of abuse. Demonstrated nonlinear pharmokinetics.
Levetiracetam	Level 1 evidence of non-efficacy.		No consistent evidence of efficacy in treating SCI related pain. May cause agitation.
Carbamazepine and Oxcarbamazepine			Oxcarbamazepine has improved tolerance and fewer side effects than carbamazepine. Carriers of the HLA-B*1502 allele, more prevalent in Asian ethnicities, are at increased risk of Stevens-Johnson syndrome. Carbamazepine is considered teratogenic. Adverse reactions may include hematologic suppression (monitor CBC), electrolyte abnormalities (monitor blood chemistry) and hepatic dysfunction (monitor LFTs)
Lamotrigine	Level 2 evidence for incomplete SCI	2nd line treatment	May be particularly efficacious treating incomplete spinal cord injuries. Lamotrigine may cause a decrease in fetal folic acid levels which is associated with neural tube malformation. Carries risk for developing severe rashes. Should be started at a low dose and titrated slowly to minimize the risk of rashes.
Valproic Acid	Level 2 evidence of non-efficacy.		No consistent evidence of efficacy in treating SCI related pain.
Topiramate			Efficacy is unclear. Unique side effect of weight loss, word-finding deficits and renal calculi.
Tricyclic Antidepressants	Level 1 evidence when comorbid depression is present. (Amitriptyline)		Often considered a first-line medication. Associated with anticholinergic side effects and QT prolongation.
Selective Serotonin and Norepinephrine Reuptake Inhibitors	Level 1 evidence of non-efficacy. (Duloxetine)		A trend toward decreasing pain was found amongst those taking duloxetine.
Selective serotonin reuptake inhibitors			Have not been found to have significant efficacy in the treatment of SCI related pain.
Trazodone	Level 1 evidence of non-efficacy.		Has not been found to have significant efficacy in the treatment of SCI related pain.
Bupropion			Has not been evaluated in the treatment of spinal cord injury-related pain but has been found to have an analgesic effect in the treatment of neuropathic pain of various etiologies but not of nociceptive pain. May lower seizure threshold.
Lithium			Requires further study.
Nonsteroidal Anti-Inflammatory Drugs			Have a role in the treatment of nociceptive and other non-neuropathic pain that may be experienced after SCI.
Acetaminophen			Has not been found to have significant efficacy in the treatment of SCI related pain but may potentiate other medications.
Tramadol	Yes	2nd line treatment	Found to have efficacy in the treatment of neuropathic pain but should be treated as an opioid medication in terms of patient selection and monitoring.
Cannabinoid Medications	Level 1 evidence of non-efficacy of dronabinol.		Conflicting evidence for analgesia for various cannabinoid substances.
Mexilitine	Level 1 evidence of non-efficacy		No evidence of efficacy and carries serious proarrhythmogenic side effects.
Calcitonin			More study is required.

Methods

The Ovid^© Medline database was searched for “spinal cord injury” and “pain” with the subheading “drug therapy.” Three-hundred and fifty results were found. These were then limited to “English,” “human” and limited from the year 2000 through 2018. One-hundred and eighty-five citations remained. These were manually screened for relevance and 43 were found to be relevant to the topic presented. Works cited by the selected papers and additional articles discussing key related topics were explored when necessary to better understand the information discussed. That material was then incorporated into this paper as well. In addition, medication package inserts were reviewed for information especially pertinent to the treatment of spinal cord injury-related pain. There was no differentiation made as to the nature of the SCI related pain when selecting papers for inclusion.

Discussion

Topical medications

Topical medications have a limited role in the treatment SCI pain below the level of injury as the affected sites often extend beyond an area to which a medication could practically be applied topically. Topical medications may have a role, however, in ameliorating pain in limited discrete areas such as peri-incisional pain or comorbid musculoskeletal pain.

Lidocaine

Topical lidocaine is available in patches, creams and ointments. The patches are available in a prescriptive 5% formulation and an over-the-counter 4% formulation. The patches do not cause cutaneous anesthesia whereas the creams and ointments may.²⁰ The patches may, however, cause local irritation which is usually mild and self-limited.²¹ The skin should be monitored when starting lidocaine patches, particularly if the patches are being placed on areas of unreliable sensation and they should only be placed on closed skin. Tachyphylaxis is achieved rapidly and the use of topical lidocaine is recommended for only 12 h in a 24 h period.²¹ The role of topical lidocaine in individuals with SCI related pain is limited and not well studied. It may be best used to avoid autonomic dysreflexia when noxious stimulation is anticipated or when addressing small areas of discrete pain. Toxicity from topical lidocaine is rare and best mitigated by using the lidocaine as directed, avoiding accidental ingestion and proper disposal of used patches. Signs of toxicity include light-headedness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, and could proceed to altered mental status and cardiovascular collapse.²¹ The dose of lidocaine should never exceed 600 mg (or 4.5 mg/kg (2 mg/lb) of body weight in children) over any 12 h period.²² Toxicity can be confirmed by testing plasma levels.²¹

Capsaicin

Capsaicin is a topical medication that destroys cellular integrity and impairs the function of nerve fibers involved in pain transmission for a prolonged period. A small case series found that 8% capsaicin patches applied after pretreatment with prilocaine showed promising results in reducing the level of pain.²³ The case series included two individuals, both of whom had suffered motor incomplete lesions. It is unclear as to how well the findings could be extrapolated to those with different types of injury. The use of capsaicin must be considered with caution in those with poor dexterity or truncal balance, to avoid its inadvertent placement in the mouth or eyes.

Antiepileptic drugs

Antiepileptic drugs (AED) have long been used in the treatment of neuropathic pain. Currently, the only medication with a United States Food and Drug Administration indication for the treatment of neuropathic pain related to spinal cord injury is pregabalin, an AED.

Pregabalin

Pregabalin affects the voltage-gated calcium channel complexes and the presynaptic terminal yielding a decrease in neurotransmitter release.²⁴ Pregabalin is effective at 100–150 mg per day in divided doses with a maximum dose of 600 mg per day.^25,26 The dose must be adjusted for renal insufficiency.²⁷ Approximately 80% of 108 individuals treated with pregabalin reported improvement when compared to 112 control subjects.²⁸ In a study of 137 individuals who were given pregabalin with 12-weeks of follow-up, a significant reduction of pain level was found.²⁵ Pregabalin is associated with several common side effects including somnolence (30% to 40%), peripheral edema (15%), and dizziness.²⁶ Pregabalin has also been associated with weight gain and abnormalities of thought processing.²⁷ AED have been associated with increased risk of falls^29–31 which can be particularly significant in the SCI population due to a propensity for balance and gait deficits, if ambulatory. Pregabalin is associated with metabolic syndrome,³² depression,^33,34 and suicide.^27,35 The side effects of pregabalin are generally dose-related with edema being a notable exception.³⁶ Pregabalin has recently become available in a generic formulation.

Though there are no specific guidelines for monitoring for suicidality when initiating or titrating pregabalin, it would seem prudent to discuss this potential side effect with the patient and their caregivers and to have early follow-up after dose changes are made as there is a concomitant increased risk of suicide due to the SCI.³⁷ The potential for suicidality is a commonly listed side effect of many of the AED and antidepressant medications listed below and similar caution would likely be prudent.

Gabapentin

Gabapentin is structurally similar to pregabalin and also acts upon calcium channels at the neural bouton. Activation of these voltage-gated channels yields an inhibitory effect upon calcium influx. Gabapentin is typically started at a low dose and gently titrated upward to a maximum daily dose of 3600 mg, divided over 3–4 doses. An effective dose is thought to be a minimum of 1800 mg per day.³⁸ Gabapentin is renally excreted and must be dosed accordingly. In its instant release form, gabapentin demonstrates nonlinear pharmokinetics. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in three divided doses, respectively.³⁹ Given the complicated absorption, long-acting formulations of gabapentin were developed. They have the advantage of once a day dosing though at of the time of this writing, the long-acting formulations are only available in brand name formulations and the dosing is not directly relatable to the instant release formulation.

Though there are studies to the contrary,^40,41 gabapentin has generally been found to ameliorate neuropathic pain of various etiologies in multiple studies^42–47 and is considered a first-line option in the treatment of SCI related neuropathic pain.^43,48–50 It is unclear if gabapentin is significantly different in terms of its efficacy when compared to pregabalin.^26,45,51 Their adverse effects are similar.³⁹ There is growing concern that gabapentin and pregabalin can be abused^52,53 and it is recognized that the concurrent use of gabapentin and opioids increases opioid potency.⁵⁴ This last effect can be used to the clinician’s advantage to maximize analgesia and reduce opioid dosing but may also exacerbate the potential lethality of opioids consumed.⁵⁵

Levetiracetam

Levetiracetam is an AED commonly used as post-traumatic seizure prophylaxis. Its mechanism of action is not well understood but may increase the effects of GABA- and glycine-gated currents and partially inhibit N-type calcium channels⁵⁶ Levetiracetam has not been found to be efficacious in the treatment of SCI pain.^57,58 A study of 24 individuals with SCI related pain found that levetiracetam was well tolerated but failed to have any efficacy on the patients’ pain levels.⁵⁷ Similarly, a Cochrane review of the use of levetiracetam in various neuropathic pain syndromes found no consistent evidence of efficacy.⁵⁹

Carbamazepine and Oxcarbamazepine

Carbamazepine and oxcarbamazepine are AEDs that affect sodium voltage-gated channels. They have been used to treat neuropathic pain of various etiologies.⁶⁰ Oxcarbamazepine has improved tolerance and is associated with fewer side effects than carbamazepine.⁶¹ Oxcarbamazepine has been found to be more effective than pregabalin when non-evoked pain is present and described as electrical, burning, and pricking pain but is less effective for other types of neuropathic pain descriptions. Different phenotypes of neuropathic pain may respond differently to various antiepileptic drugs.²⁴ Carbamazepine has serious hematologic side effects. While carbamazepine is considered teratogenic, the risk for the fetus exposed to oxcarbazepine is not well understood. Carriers of the HLA-B*1502 allele, more prevalent in individuals of Asian descent, are at heightened risk of Stevens-Johnson syndrome when taking oxcarbamazepine.⁶²

Lamotrigine

Lamotrigine is an AED that affects voltage-gated sodium channels. In a 3 week study of 147 individuals with SCI related pain, lamotrigine was found to have efficacy comparable to that of amitriptyline.⁶³ Another study suggested that lamotrigine is particularly efficacious in the setting of an incomplete spinal cord injury.⁶⁴ Lamotrigine carries a “black box” warning regarding the risk for developing severe rashes. Due to the risk of serious adverse effects, lamotrigine must be very slowly titrated to the desired, effective dose (usually 200–400 mg per day).³⁸ The proposed dosing schedule is: 25 mg/d for 2 weeks then increase to 25 mg twice daily for 2 weeks, then increase weekly by 25 mg twice daily to goal of at least 100 mg twice daily.³⁸ The regimen may have to be altered depending upon other medications, particularly other AEDs, that are being used concurrently.⁶⁵ There are concerning animal studies regarding safety during pregnancy, however, lamotrigine is not known to be specifically teratogenic. Lamotrigine may cause a decrease in fetal folic acid levels, a condition associated with neural tube malformation.⁶⁶

Valproic acid

Valproic acid is a first-generation AED that acts upon sodium channel mechanisms. A double-blind crossover study found no significant difference in pain between treatment and non-treatment groups after 3 weeks.⁶⁷

Topiramate

Topiramate is another AED that exerts an effect upon voltage-gated sodium channels, and to a lesser extent, calcium channels and GABA channels and may inhibit glutamate transmission. Evidence for efficacy in the treatment of SCI pain is conflicted, though the varied results may be related to dosing levels achieved.⁶⁸ Starting this medication at 25 mg twice a day with a target dose of 100 mg twice a day has been proposed,⁶⁸ the usual maximum dose is 400 mg per day.⁶⁹ Topiramate has a unique side effect of weight loss, which could be of benefit to overweight patients but may be detrimental to patients suffering from post-traumatic cachexia or wounds. Topiramate is associated with cognitive deficits, particularly with word-finding deficits.⁷⁰ Due to a carbonic anhydrase inhibitory effect, topiramate use is associated with renal calculi, a condition already more common in some spinal cord injury populations. Appropriate hydration is recommended when taking topiramate.⁷⁰ Also related to topiramate’s effects upon the renal system, it interacts with many commonly used medications such as metformin (increased risk of lactic acidosis) and aspirin (increased risk of salicylate toxicity and metabolic acidosis).⁷¹ Individuals with SCI have a higher risk of metabolic syndrome and may use metformin and aspirin for primary or secondary prevention of diabetes and cardiac disease, respectively. Ethanol must be used very judiciously with all medications, particularly with CNS depressant treatments, it is contraindicated with an extended-release formulation of topiramate.⁷¹ Topiramate is associated with acute myopathy, fluctuation in intraocular pressures, diminished efficacy of oral contraceptive medications, and may be teratogenic causing cleft lip/palate.⁶⁹ Topiramate may cause oligohidrosis and the resultant hyperthermia which is of special concern to those with a SCI who have difficulty with thermoregulation.⁶⁹

Antidepressant medications

Tricyclic antidepressants

Tricyclic antidepressants (TCA), represented by amitriptyline, a tertiary amine TCA, have classically been used to treat neuropathic pain of various etiologies. Amitriptyline has been demonstrated to ameliorate levels of SCI related neuropathic pain and is often considered a first-line treatment on par with gabapentin and pregabalin.^50,72 A crossover study with gabapentin and diphenhydramine (as an active placebo) demonstrated efficacy of amitriptyline in treating spinal cord injury-related pain,⁴⁰ however, the results of TCA trials are not all positive.^73–75 The risk to benefit ratio should be considered on an individual basis. Patients who suffer from pain and concomitant depression are most likely to benefit from a TCA.⁷⁶ TCAs are associated with multiple side effects including sedation, dry mouth, constipation, cardiac arrhythmias, glaucoma, urinary retention and weight gain. These side effects can be favorable to the patient if difficulty sleeping, urinary leakage or oral secretion management are problematic. Amitriptyline has been associated with an increase in spasticity.⁷⁶ Secondary amine TCA medications include imipramine and nortriptyline and are generally better tolerated and may be of similar potency.⁴⁴ All TCA medications are on Beer's Medication List that are to be avoided in the geriatric population⁷⁷ thus the side effect profile and potential for polypharmacy must be especially scrutinized in the geriatric patient. ECG screening for QT prolongation is recommended in older patients and for those with cardiac comorbidities as TCAs are associated with an increased risk of arrhythmias. The usual starting doses for amitriptyline and nortriptyline are between 10 mg and 25 mg each night. Therapuetic doses from 50 mg to 150 mg each night have been proposed.^38,40,74,78 At high doses (>100 mg/day) TCAs are associated with an increased risk of cardiac arrest.⁷⁹

Selective serotonin and norepinephrine reuptake inhibitors

It is postulated that norepinephrine reuptake inhibition correlates positively with pain control and that selective serotonin and norepinephrine reuptake inhibitors have efficacy in the management of pain. In a double-blind randomized study involving 48 individuals with neuropathic pain of a central etiology,⁸⁰ a trend toward decreasing pain was found amongst those taking duloxetine. The dose of duloxetine was titrated up to 120 mg per day, though the usual approved dose is 60 mg per day. Only one domain in a 36-Item Short Form (SF36) survey (body pain) demonstrated a significant decrease in pain. Secondary outcomes such as pain-related disability showed no significant change.

Another selective serotonin and norepinephrine reuptake inhibitor is venlafaxine, available in regular and extended-release formulations. A randomized controlled study demonstrated efficacy of venlafaxine ER in alleviating nociceptive but not neuropathic pain in 123 individuals who suffered from spinal cord injury and concomitant depression with a dose of 150 mg per day or higher showing efficacy.⁸¹

Duloxetine and venlafaxine carry black box warnings regarding an association with suicidal behaviors.^{82, 83} Although these medications are likely most efficacious in the depressed person, screening for suicidal ideation and requesting close follow-up upon initiation and titration of all antidepressant medication appears prudent. Duloxetine is associated with orthostatic hypotension and increased bleeding when combined with nonsteroidal anti-inflammatory drugs and anticoagulants.⁸² Spinal cord injured patients are at increased risk of orthostatic hypotension due to disruption of autonomic reflexes and vascular pooling.⁸⁴ Duloxetine is made in capsule form and use via a gastrostomy tube is not recommended by the manufacturer.⁸² Venlafaxine is associated with similar adverse reactions to duloxetine.^44,83 The usual starting dose of duloxetine is 20 mg to 30 mg and it is then increased after one week to avoid gastroenterological side effects associated with higher starting doses.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors have not been found to have significant efficacy in the treatment of SCI related pain.⁸⁵

Trazodone

Trazodone is an atypical antidepressant with strong serotonin reuptake inhibition and, to a lesser degree, norepinephrine reuptake inhibition. Trazodone does not have significant efficacy in the treatment of SCI related pain. A double-blind placebo-controlled study demonstrated that trazodone was no better than placebo in controlling pain but was associated with more side effects causing dropout from the study.⁸⁶

Bupropion

Bupropion is an antidepressant that inhibits the reuptake of dopamine and norepinephrine. Several studies have documented an analgesic effect of bupropion in the treatment of neuropathic pain of various etiologies,^87–89 but bupropion does not appear to have been evaluated for the treatment of spinal cord injury-related pain specifically. Bupropion lowers seizure threshold and should be avoided in patients at risk for seizure activity. This is a particular consideration in the SCI population due to high prevalence of concomitant brain injury.

Lithium

Lithium, commonly utilized as a mood stabilizer, was recently studied in China for potential as a neuroregenerative agent, and though no such effect was found, it seemed to decrease neuropathic pain.⁹⁰ Animal studies have also suggested efficacy in the treatment of neuropathic pain.⁹¹ The mechanism of analgesia is not well understood though lithium may play a role in the selective regulation of neurotrophins.⁹⁰ Lithium is associated with a variety of serious side effects and its use in the treatment of pain is not yet well accepted. There are no established dosing guidelines for the use of lithium in the treatment of pain. The therapeutic level needed to treat psychiatric conditions is very close to the toxic level. Signs of toxicity include vomiting, drowsiness, muscular weakness and lack of coordination, giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine. Chronic lithium uses can cause renal impairment which may mimic diabetes insipidus. Lithium should generally not be given to patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, and to patients receiving diuretics as the risk of lithium toxicity is very high in these patients. Lithium is considered to be teratogenic.⁹² Despite its drawbacks, further study should be revealing as to the role of lithium in the treatment of recalcitrant SCI related pain.

Nonsteroidal anti-Inflammatory drugs and Acetaminophen

NSAIDs

NSAIDs are not considered to have efficacy in the treatment of neuropathic pain⁹³ but may have a role in the treatment of nociceptive and other pain that may be experienced after SCI. Nonsteroidal anti-inflammatory drugs affect bone metabolism and are often avoided during the healing process after spinal fusion surgery.⁹⁴ Chronic nonsteroidal anti-inflammatory drug use has been linked to cardiac disease, hypertension, renal pathology, bleeding tendencies, gastritis and gastric hemorrhage.⁹⁵

Acetaminophen

Acetaminophen is often used by patients with SCI but it has not been found to have significant efficacy in the treatment of SCI related pain.^16,96 Nonsteroidal anti-inflammatory drugs and acetaminophen are often formulated in combination with opioid medications and likely potentiate their effects.⁹⁷

Miscellaneous medications

Tramadol

Tramadol is a unique medication that has a weak opioid agonist effect with weak monoamine reuptake inhibition. Tramadol is discussed in this paper as it has not been historically considered a true opioid. In a crossover study, tramadol was found to have efficacy in the treatment of neuropathic pain.⁹⁸ Because of its effect on opioid receptors, tramadol is considered an opioid medication with the associated side effects and psychosocial issues, though at a more moderate level.⁸⁵ It is generally considered a first or second-line option when treating neuropathic pain.^50,85 Tramadol is associated with side effects similar to TCA and opioid medications. It is serotonergic and is known to lower the seizure threshold. Tramadol should be started at a low dose and titrated gradually to a maximum dose of 400 mg per day of the instant release formulation⁹⁹ or 300 mg per day of the sustained release formulation.¹⁰⁰

Cannabinoid medications

There is an advancing availability and interest in cannabinoid medications. In a postal survey conducted by Cardenas and Jensen,¹⁶ marijuana use was found to have the best self-reported analgesic results of all the treatments mentioned. Small studies have shown promise¹⁰¹ but have not demonstrated consistent results when marijuana or its extracts were used to treat SCI related pain and marijuana may even increase pain levels.¹⁰² A recent Cochrane review¹⁰³ found very low-quality evidence of analgesia when using various preparations of cannabis-based medications to treat chronic neuropathic pain. The review was not specific to SCI related pain, included various cannabis-related medications and routes of administration without standardization. There were no high-quality studies included.

Confusing the clinical picture for the role of cannabinoid medications is that whole marijuana is composed of many compounds including Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabis terpenoids and flavonoids with little standardization available of either the product or the research evaluating it.¹⁰⁴ THC is associated with a wide range of psychoactive effects, including feeling ‘high’, anxiety, paranoia, perceptual alterations, and cognitive deficits, particularly deficits in verbal recall and exacerbates psychotic symptoms in patients with schizophrenia.¹⁰⁵ It has been postulated that CBD may have a greater analgesic effect than THC without any psychoactive adverse effects and may even be protective of psychiatric events.^104,105

Dronabinol is synthetic delta-9-tetrahydrocannabinol (delta-9-THC) with FDA indications for the treatment of nausea associated with chemotherapy and for appetite stimulation in the setting of HIV/AIDS.¹⁰⁶ A trial studying the effects of dronabinol, as compared to active controls, found no efficacy in the treatment of SCI related pain.¹⁰⁷ Sativex^® (GW Pharmaceuticals) is an oromucosal whole cannabis-based spray combining THC with CBD, minor cannabinoids and terpenoids. An unpublished study of 117 spinal cord injured individuals were treated with Sativex^® for 10 days. There was no significant change in numerical rating scale pain scores, but improvements in Brief Pain Inventory and Patients Global Impression of Change were noted.¹⁰⁴ This medication is in phase 2 studies in the United States.¹⁰⁸

There is significant controversy regarding the legalization of cannabis-related medications, the presence of withdrawal symptoms and the severity of its adverse side effects. These issues are beyond the scope of this paper. As additional cannabinoid medications and “medical marijuana” become available and as the research advances, the role for cannabinoid medications will be better elucidated.

Mexilitine

Mexilitine is an oral sodium channel blocker that has been used to treat neuropathic pain in the past. It has not been found to be effective in treating SCI related pain¹⁰⁹ and its use is advised against by the CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord.⁵⁰ Mexilitine is proarrhythmogenic.

Calcitonin

Calcitonin is a polypeptide secreted by the thyroid gland and effects control upon body blood calcium levels and bone calcium metabolism. Calcitonin derived from salmon is commonly used therapeutically and is indicated in the treatment of hypercalcemia and Pagets’ disease in its subcutaneous and intramuscular injection form¹¹⁰ and for postmenopausal osteoporosis in both the injectable and nasal spray forms.^110,111 Calcitonin has also been found to have an analgesic effect upon various pain syndromes including phantom limb pain, neuropathic pain, pain due to metastatic bone disease and vertebral compression fractures. The mechanism of analgesic action is not well understood and multiple possibilities have been suggested including an effect upon serotonin levels, inhibition of prostaglandin and thromboxane synthesis and increasing beta-endorphin levels.¹¹² A three-person case series found efficacy in the administration of calcitonin for SCI related neuropathic pain but not nociceptive pain.¹¹² Further study is needed to better understand the role of calcitonin as an analgesic agent and to establish a recommended dosing routine.

Conclusion

SCI pain is a complex multifactorial entity that has a significant impact on the health and quality of life of individuals with spinal cord injuries. With a growing regulatory, public health, and scientific awareness of the adverse consequences of chronic opioid therapy, renewed emphasis must be placed upon non-opioid treatment options for SCI related pain. Though many such options exist, each medication has its own unique combination of advantages and pitfalls for any given individual. By understanding the intricacies of the medications and the medical complexities of the patient, prudent drug choices can be made. The general categories of medications available to choose from include antiepileptic and antidepressant medications. Pregabalin, gabapentin and TCA medications have the largest body of literature to support their use. Duloxetine should be considered in individuals with comorbid depression. Various pain sensations may respond to different medications and combinations of medications may be required to treat recalcitrant pain. Further investigation is required to better understand the place calcitonin, lithium, and marijuana have in treating SCI related pain. Research in the future should explore matching an individuals’ genotype and pain phenotype to specific treatments.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Disclaimer statements

Contributors None.

Funding None.

Conflicts of interest There are no conflicts of interest or financial interests to disclose by the authors.