Alternatives to Opioids in Medication for Pain

Alternatives to Opioids in the Pharmacologic Management of Chronic Pain Syndromes: A Narrative Review of Randomized, Controlled, and Blinded Clinical Trials – free full-text /PMC5785237/ – 2018 Nov

This recent review finds that there is very little evidence beyond a few weeks for the “effectiveness” [see qualification at end of review] of any non-opioid medication that has some beneficial effect on pain.

The goal of this review was to report the current body of evidence-based medicine gained from

• prospective,
• randomized-controlled,
• blinded studies

on the use of non-opioid analgesics for the most common non-cancer chronic pain conditions.   

Chronic pain exerts a tremendous burden on individuals and societies.

If one views chronic pain as a single disease entity, then it is the most common and costly medical condition.

A total of 9566 studies were obtained during literature searches and 271 of these met inclusion for this review

Overall, while many non-opioid analgesics have been found to be effective in reducing pain for many chronic pain conditions,

it is evident that the number of high-quality studies is lacking and the effect sizes noted in many studies is not considered to be clinically significant despite statistical significance

Effect sizes can be seemingly large, and yet not be of clinical significance. There’s a big difference between the two.

Utilization of rigorous and homogeneous research methodology would likely allow for better consistency and reproducibility, which is of utmost importance in guiding evidence-based care.

recent guidelines from the Centers for Disease Control (CDC) have recommended that the use of opioids for non-malignant chronic pain be used only in certain circumstances

Introduction

Many practitioners rely on non-opioid medications to treat chronic pain, however, for some patients; opioid analgesics are utilized for the symptomatic treatment of chronic pain.

Opioid prescriptions increased per capita by 7.3% from 2007 to 2012.

This is completely expected as the population both increases and ages, yet everyone behaves like this is a completely unacceptable situation.

The goals of this review are to provide the reader with data from prospective, randomized, controlled, and blinded clinical trials where non-opioid medications were investigated for the treatment of chronic pain.

Findings from Studies Grouped by Chronic Pain Syndrome

Chronic Low Back Pain (CLBP)

Chronic low back pain (CLBP) is one of the most commonly encountered conditions in clinical practice. Despite its prevalence, it is a condition that leads to high medical utilization and disability and, unfortunately, there are few effective interventions

Despite the fact that CLBP is the second most common reason that symptomatically drives people to see their physicians, there are no on-label FDA approved medications for this condition.

The treatment of CLBP includes the use of a variety of prescription medications that do not have FDA approval for CLBP (Table 2) [below].

Table 2

Chronic Low Back Pain – Effective Medications based on Included Studies

Chronic Low Back Pain – Effective Medications
FDA On-Label	Off-Label
Acetaminophen
None	None
NSAIDs
None	Naproxen, Etoricoxib, Valdecoxib, Rofecoxib, Celecoxib, Diclofenac, Piroxicam, Indomethacin
ARIs
None	Desipramine, Doxepin, Nortriptyline, Duloxetine, Maprotiline
Membrane Stabilizers
None	Topiramate
Muscle Relaxants
None	Carisoprodol, Cyclobenzaprine, Diazepam
ARI/Opioid
None	Tramadol, Tramadol/acetaminophen, Tapentadol
Topical Capsaicin
None	Capsaicin cream
Local Anesthetics
None	None
NMDA Antagonists
None	None
Miscellaneous
None	Botulinum Toxin Type A, Tanezumab

FDA: Food and Drug Administration; NSAIDs: non-steroidal anti-inflammatory drugs; ARI: amine reuptake inhibitor; NMDA: N-methyl-D-aspartate

Myofascial Pain Syndrome (MPS)

Myofascial pain syndrome (MPS) is a common painful condition encountered in the general population. It is a localized muscle condition that presents with skeletal muscle pain and stiffness

The exact pathophysiology and etiology of myofascial trigger points and myofascial pain syndrome is still unknown. Despite MPS being quite common, they are most often under-diagnosed or misdiagnosed conditions. The treatment of MPS includes the use of prescription medications, however, no medications are specifically FDA-approved for MPS, although many muscle relaxants have indications for muscle spasm. The treatment of MPS includes the use of a variety of prescription medications that do not have FDA approval for MPS (Table 3) [below].

Myofascial Pain Syndrome – Effective Medications based on Included Studies

Myofascial Pain Syndrome – Effective Medications
FDA On-Label	Off-Label
NSAIDs
None	IM Diclofenac (short-term relief), Topical Diclofenac Sodium patch
ARIs
None	None
Membrane Stabilizers
None	None
Muscle Relaxants
None	Methocarbamol
ARI/Opioid
None	None
Topical Capsaicin
None	None
Local Anesthetics
None	Topical Lidocaine Patch, 0.5% Bupivacaine IM injection
NMDA Antagonists
None	None
Miscellaneous
None	Botulinum Toxin Type A

FDA: Food and Drug Administration; NSAIDs: non-steroidal anti-inflammatory drugs; ARI: amine reuptake inhibitor; NMDA: N-methyl-D-aspartate

Fibromyalgia (FM)

Fibromyalgia is the second most common “rheumatologic” disorder, second only to osteoarthritis79. Depending on the diagnostic criteria used, the prevalence is from 2 to 8% of the general population79. Pain in FM is often widespread and can be challenging and difficult to control. The treatment of FM includes the use of a variety of prescription medications that have FDA-approval for FM and those that do not (Table 4) [below].

Fibromyalgia – Effective Medications based on Included Studies

Fibromyalgia – Effective Medications
FDA On-Label	Off-Label
NSAIDs
None	None
Amine Reuptake Inhibitors (ARI)
Duloxetine, Milnacipran	Amitriptyline, Fluoxetine,Paroxetine (controlled-release)
Membrane Stabilizer
Pregabalin	Gabapentin
Muscle Relaxants
None	Cyclobenzaprine
ARI/Opioid
None	Tramadol/acetaminophen
Opioid Antagonists
None	Low-dose Naltrexone
NMDA Antagonists
None	Memantine
Local Anesthetics
None	None
Miscellaneous
None	Nabilone

FDA: Food and Drug Administration; NSAIDs: non-steroidal anti-inflammatory drugs; ARI: amine reuptake inhibitor; NMDA: N-methyl-D-aspartate

Post-herpetic neuralgia (PHN)

PHN develops after the reactivation of the herpes zoster virus (HZ) from its latent state. The incidence of HZ reactivation in the United States is around 500,000 cases per year or approximately 2 cases per 1000 persons. Patients over 70 years of age with HZ have a 50% risk of developing PHN whereas patients under 40 years of age rarely develop it. The treatment of PHN includes the use of prescription medications that have FDA-approval for PHN management and those that do not (Table 5).

Post-herpetic Neuralgia – Effective Medications based on Included Studies

Post-herpetic Neuralgia – Effective Medications
FDA On-Label	Off-Label
Topical (non-local anesthetic)
Capsaicin 0.025%; 0.075%; 0.025%–10%–25%; 0.035%; 0.1%; 8%; 0.25%; Capsaicin Patch (8%)	None
Amine Reuptake Inhibitors (ARI)
None	Amitriptyline, Desipramine, NortriptylineFluoxetine
Membrane Stabilizers
Gabapentin, Gabapentin GR, Gabapentin Enacarbil, Pregabalin	Levetiracetam
ARI/Opioid
None	Tramadol
Local Anesthetics
Lidocaine Patch (5%)	None
NMDA Antagonists
None	None
Miscellaneous
None	Botulinum Toxin Type A

FDA: Food and Drug Administration; ARI: amine reuptake inhibitor; NMDA: N-methyl-D-aspartate

Painful Diabetic Neuropathy (PDN)

The World Health Organization estimates 150 million people had diabetes in the year 2000 and project 366 million by the year 2030. The prevalence of peripheral neuropathy in patients with diabetes was 43%, and higher in type 2 (51%) than in type 1 (26%). The treatment of PDN includes the use of prescription medications that have FDA-approval for PDN management and those that do not (Table 6).

Painful Diabetic Neuropathy – Effective Medications based on Included Studies

Painful Diabetic Neuropathy – Effective Medications
FDA On-Label	Off-Label
Topical (non-local anesthetic)
Capsaicin 0.025%; 0.075%; 0.025%–10%–25%; 0.035%; 0.1%; 8%; 0.25%	Clonidine
Amine Reuptake Inhibitors (ARI)
Duloxetine	Desipramine, Imipramine, Amitriptyline,Venlafaxine, Paroxetine
Membrane Stabilizers
Pregabalin	Gabapentin, Topiramate, Lamotrigine, Oxcarbazepine, Zonisamide
ARI/Opioid
Tapentadol ER	Tramadol
Local Anesthetics
None	Mexiletine
NMDA Antagonists
None	Dextromethorphan
Miscellaneous
None	Intradermal Botulinum Toxin Type A,Cannabis, Nabilone

FDA: Food and Drug Administration; ARI: amine reuptake inhibitor; ER: extended release; NMDA: N-methyl-D-aspartate

I’ve had some success with these drugs, so I include more details:

Membrane Stabilizers

Pregabalin (300mg/daily) has been shown to reduce ‘worst possible’ pain intensity by 1.5 points (NRS) and 1.6 (VAS) 1 week after treatment inception which remained significant during the course of an 8-week multicenter PC-RCT. Furthermore, it improved mood, reduced sleep interference, and was associated with a significant impression of improvement assessed by the patient and clinician.

I’ve had good luck using this as a “breakthrough” medication instead of daily as prescribed (technically, this mean I’m abusing my pain medication), thanks to a tip from another pain patient.

Usually, I have a variety of specific local muscle and joint pains where structures have become misaligned or unstable. For this kind of nociceptive pain, opioids are effective for me.

On about 2 or 3 days a week, I also suffer body-wide aching which does not respond sufficiently to my usual opioid dose. Then I take 300mg Lyrica (pregabalin), which does a remarkable job in easing my all-over pain for the rest of the day.

Because my body isn’t used to the medication on a daily basis, a sudden large dose like this can lead to sometimes severe dizziness, so I can only take it at home – be warned!

In a separate trial, 52% of patients with baseline pain intensity in the high moderate to severe range had >50% relief compared to 24% in the placebo group over a 12 week RCT yielding a number needed to treat (NNT) of 3.6. Similar positive results have been seen in PC-RCTs in China, Canada, Japan, Europe and Korea.

Gabapentin has been shown to be effective in the reduction of pain intensity and improvements in mood, sleep, quality of life. The minimal effective dose ranged from 1800 – 2400 mg/daily.

I tried this drug and noticed absolutely nothing, so I switched to Lyrica instead and found relief with that.

Topiramate has been shown to be borderline effective in the reduction of pain intensity, improvement in sleep interference, quality of life, and mood in two PC-RCTs. In the positive trials, the pain reduction occurs within 8 weeks.

Lamotrigine has been shown to be minimally effective in the reduction of pain intensity in two PC-RCTs and no change in one. Subjects had no improvement in sleep interference, quality of life, patient reported improvement in pain, or mood. In the positive trials, the minimal effective dose ranged from 400 mg/daily and pain reduction occurs within 6 weeks.

Oxcarbazepine has been shown to be borderline effective in the reduction of pain intensity in a single PC-RCT, but no different in two PC-RCTs. The pain reduction occurs within 2 weeks. The minimal effective dose in the single positive study was 1800 mg/daily.

Amine Reuptake Inhibitors (ARIs)

Duloxetine has been shown to be effective in the reduction of pain intensity, improvement in sleep interference due to pain, quality of life, patient and clinician reported improvement in pain and mood in PC-RCTs. The pain reduction occurs within 1 week. Pain relief was found to be dose dependent and the minimal effective dose was 60 mg/daily.

I tried Duloxetine and it made me almost psychotic after only a week at even 20mg/daily. When I tried to come off it, the brain-zaps were intense, so I’m grateful I was only on such a low dose for such a short time.

Venlafaxine has been shown to be effective in the reduction of pain intensity, patient and clinician reported improvement in pain in PC-RCTs. The pain reduction occurs within 2 or 6 weeks and the NNT was 4.5. The minimal effective dose ranged from 150–225 mg/daily.

I’ve been taking this since 1991 and it definitely helps my depression at 150mg/day. My doctor once had me try doses up to 450mg/day once, but it still didn’t help my pain. If I try to cut back, the brain-zaps show up by late afternoon.

The TCAs desipramine, imipramine and amitriptyline, have demonstrated effectiveness in the reduction of pain intensity and improvement in sleep interference. The pain reduction occurs within 3–5 weeks. Pain returned within 2 weeks of TCA discontinuation.

Pain relief was independent of depression and there was no effect on mood by either amitriptyline or desipramine except in a single desipramine trial. The minimal effective dose ranged from 90–150 mg/daily and the effects of amitriptyline were dose dependent to 150mg/daily.

Paroxetine, but not fluoxetine, reduce the pain intensity of DPN, improvement in sleep interference and improve nighttime pain. The pain reduction occurs within 1–5 days. The minimal effective dose ranged from 40–50 mg/daily.

Conclusions

The scope of this review on non-opioid pharmacotherapy was broad and all-encompassing for the most common chronic pain syndromes that current pain management physicians treat

Considering 2468 articles were screened and strict inclusion criteria were employed, the paucity of high quality prospective, blinded, RCTs investigating the pharmacologic therapies that are so commonplace in our field was disappointing (Supplemental Table 1).

The effect sizes for many treatments were small, including some of those that are FDA-approved.

IMMPACT guidelines have reported on the changes in pain scores that are consistent with a “significant” improvement in pain – a change of 30% in numerical pain rating or more.

Many of the studies presented here do not provide this level of reduction, yet have shown statistical significance.

Mainstays of treatment – such as NSAIDs, membrane stabilizers, muscle relaxants, and amine reuptake inhibitors – seemed to have positive findings for a few conditions, however, the robustness of pain reduction were modest at best.

The evidence base has its limitations as well, which may potentially affect the quality of the included studies.

Populations studied likely had heterogeneity even within a specific pain condition population.

Moreover, assessment of “pain outcomes” varies from study to study, which makes it difficult to compare one study to the next, even within a specific pain condition population.

Furthermore, many studies were funded by industry, for example, the manufacturer funded the majority of placebo-controlled trials of duloxetine for chronic low back pain and nearly all trials of tramadol and tapentadol.

Even with its substantial societal impact, we have not seen the type of developments in the treatment of the chronic pain that have been garnered in other fields of medicine. There are explanations and challenges in performing transformative pain research that can explain this limited progress.

• First, pain research is tragically underfunded in both the private and public sectors. This is distressing on multiple levels and likely distracts talented individuals from pursuing an academic or industry pain research career.
• Secondly, despite chronic pain being the most prevalent public health condition in the United States, the magnitude of the problem is not well-recognized by the general public, as indicated by a recent poll of U.S. adults where only 18% of respondents identified chronic pain as a major public health problem