Nonopioid Analgesic, Nonpharmacologic Options for Pain Management Reviewed


Combining nonopioid analgesics and nonpharmacologic pain management options with opioid medications can lead to better patient outcomes.

One of the problems with treating chronic pain, said Emily Leppien, PharmD, BCPS, BCPP, is that pain is a subjective disease, often without physical markers.

But more people in the United States live with chronic pain than those that live with cancer, heart disease, and diabetes, combined, said Leppien, a clinical assistant professor at the Binghamton University School of Pharmacy and Pharmaceutical Sciences and a clinical pharmacy specialist at Lourdes Pain Care in Binghamton, New York, in her presentation at the American Pharmacists Association 2022 Annual Meeting & Exposition.

“One hundred and sixteen million Americans are currently living with chronic pain,” she said, “[and] opioids should not be the default pain medication.”

Instead, Leppien said, pharmacists and prescribers should look toward both nonpharmacologic and nonopioid pharmacological analgesics before opioid therapy is initiated, a suggestion backed up by pain management guidelines.

Since the 2016 publication of the CDC guidelines on opioid prescribing for chronic pain, opioid prescription rates have gone down. However, Leppien pointed out, decreased prescribing does not equal decreased pain.

“Even though we have seen a trend downward in the number of opioid prescriptions that are being dispensed or being prescribed, [the] same number of patients still have chronic pain,” she said. “How are those patients being managed?"

A multimodal approach is the best answer, Leppien suggested, perhaps beginning with nonopioid analgesics and progressing to combination therapies, low-dose opioids plus nonopioid analgesics, local anesthetics or peripheral nerve blocks, or long-acting opioids. Each of these steps, though, should be undertaken in addition to nonpharmacologic strategies. “As pain resolves, we can start to taper or take away medication depending on whether or not that pain acute or subacute,” Leppien explained.

There are a number of options—including topical anesthetics, gabapentanoids and antiepileptic drugs, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, opioid receptor antagonists, and antipsychotics—that may be used for nonopioid analgesic pain management, although, Leppien cautioned at the start of her presentation, many of the medications suggested are being used off-label for pain management.

When considering one of these nonopioid options, it’s important for providers to understand a patient’s complete pain picture. “Most patients are not going to have just one type of pain,” Leppien explained. “There may be an overlapping pain picture [with] patients experiencing nociceptive and neuropathic pain at the same time. Our treatment approach should target both of those types of pain.”

Topical anesthetics like capsaicin 1% cream and 8% patches or lidocaine 5% patches have some evidence indicating their effectiveness, and capsaicin 8% patches are currently FDA approved for conditions like postherpetic neuralgia and diabetic neuropathy. Within the gabapentanoid class of medications, gabapentin and pregabalin are approved for post herpetic neuralgia and neuropathic pain, diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia, respectively. While these drugs can be a good choice for the right patient—they tend to work faster and can be titrated quickly—there is an increased cost and risk of dependence.

The most studied antiepileptic drugs are carbamazepine and lamotrigine, but only carbamazepine is FDA-approved to treat trigeminal neuralgia. This class of medication can come with a number of adverse effects, ranging from anemia to thrombocytopenia.

SNRI medications do have some FDA approvals for pain—such as duloxetine, approved to treat fibromyalgia, diabetic peripheral neuropathy, and chronic musculoskeletal pain—but all come with the potential for adverse effects that include nausea, hypertension, loss of appetite, serotonin syndrome, sexual dysfunction, and urinary retention. Of these medications, duloxetine currently has the best clinical evidence supporting its use for pain management.

Tricyclic antidepressant options include amitriptyline and nortriptyline, neither of which have any current pain related FDA approval. While these drugs have a low number needed to treat—only 3 to 4 for a 50% reduction in pain—side effects may limit use. For patients with sleep difficulties, these drugs can be effective in addressing 2 problems through one prescription. Second generation antipsychotics—including aripiprazole, olanzapine, quetiapine, and risperidone—can potentially reduce the over-firing of dopaminergic neurons, which has been shown to potentially improve abnormal pain perceptions. In the research, these medications have shown the most efficacy in managing neuropathic pain, fibromyalgia, and headache.

Opioid receptor antagonists, Leppien noted, have also shown some efficacy in pain treatment. “Naltrexone for pain management is used at significantly lower doses than what is commercially available,” Leppien explained. “The lowest commercially available tablet is 50 mg; low-dose naltrexone for pain management is dosed 0.5 to 4.5 mgs per day.” But because it’s not commercially available at those low doses, this option does require compounding by a pharmacist.

When it comes to naltrexone, the analgesic mechanism remains unclear, with researchers still debating how, exactly, low dose naltrexone can target pain. The simplified version, she explained, is that as naltrexone binds to mu opioid receptors as an antagonist, endorphins begin to upregulate. Because endorphins are blocked from binding to the mu receptor, their production increases which increases upregulation of pain receptors—leading to a pain response.

Naltrexone dosing should be started at a lower dose and titrated up, and benefit is not typically seen immediately—sometimes requiring several weeks before patients notice a pain benefit. And, Leppien cautioned, one of the biggest clinical pearls to keep in mind is that naltrexone use can precipitate opioid withdrawal if initiated after a patient has recently discontinued an opioid therapy. “It’s ideal to taper the opioid, if a patient is on opioids first, before switching to naltrexone to be sure we don’t push the patient into withdrawal,” she said. There’s also a risk of unintentional opioid if naltrexone is used in addition to opioids, Leppien added. “The amount of opioid that would be needed to push naltrexone off of the mu receptors is going to be higher than what a patient may have previously used—or a normal dose if the patient wasn’t using naltrexone—and that can result in overdose once naltrexone is pushed off the opioid receptor.” This is particularly important to keep in mind when treating patients who may be using recreationally or illicitly using opioid therapies.

OTC dietary supplements can also be utilized as part of the nonopioid analgesic toolkit, but these options have the additional complication of not being FDA regulated or approved. “These drugs…have even more limited evidence than the drugs we’ve previously discussed,” Leppien noted, “but there is some efficacy in the literature that shows they may be useful.” These supplements include acetyl-L-carnitine, alpha-lipoic acid, glucosamine chondroitin, and magnesium.

When it comes to selecting treatment, Leppien had some advice: choose treatment options based on how the patient describes their pain, their comorbid diagnoses, and—perhaps most importantly—include patients in the decision-making process.

“If a patient isn’t going to take the medication because they’re not interested, well, that’s just a waste of everybody’s time. Including the patient in the treatment decision-making can certainly help to improve pain outcomes,” she said. Introducing nonpharmacologic strategies like acupuncture, cryotherapy, massage therapy, and cognitive behavioral therapy can also be a key part of a patient’s pain management plan.

“If we’re thinking about treating patients with nonopioid strategies, nonpharmacologic interventions should always be in addition to the use of nonopioid therapies—regardless of which step [of the pain management approach] the patient is on,” she said. “That is guideline recommended; those are guideline recommended therapies. Evidence isn’t as robust as it is with oral medication options, but it’s still worth a try.”


Leppien EE. Non-opioid options for pain management. Presented at: American Pharmacists Association 2022 Annual Meeting & Exposition; March 18-21, 2022; San Antonio, TX

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