Analgesic Use in Primary Care

Pain management in primary care is at a crossroads. While managing pain in the primary care setting is not a new endeavor, due to a rapidly aging population,^1,2 the eradication of interdisciplinary pain clinics across the country, and enhanced emphasis of the assessment and treatment of chronic pain, primary care has become the forefront in the management of chronic pain. Such care has been further driven by the US declaring the “opioid epidemic” a Public Health Emergency in 2017,³ establishing a novel set of standards in the management of chronic pain.

However, while primary care remains one of the most prevalent areas of medicine to treat pain, several challenges have risen confounding the effective management of this population of patients. These challenges include managing multiple disease states (especially in the context of an aging and more frail population), physician and provider shortages arising throughout the primary care setting because of earlier retirement and increased specialization,^4,5 as well as reducing comfortability with treating chronic pain due to continued educational and training failures across the clinical community.^6,7

Considering all of this, it is essential to review the most commonly used analgesics in the primary care setting, including their mechanisms, benefits, and risks. Opioid therapeutics are outside the scope of this article.

Topical Analgesics

Topical analgesics are often recommended first for acute and chronic pain given their accessibility in the community (most are available OTC), as well as their low risk of harm because of lower systemic absorption.⁸ While traditional US guidelines have only minimally made mention of using topical analgesics for chronic pain,^9,10 they remain the first-line recommended treatment for several pain conditions across the globe,^11-14 as well as within more recent US guidance documents.^15-17

Despite topical analgesics exhibiting minimal systemic absorption, many products have substantial evidence and efficacy for controlling pain. These include topical NSAIDs such as diclofenac and methyl salicylate, and counterirritants such as camphor, lidocaine, capsaicin, and menthol.

While NSAID mechanisms will be discussed more specifically in the following section, including the utility of diclofenac gel, it is important to recognize the growing importance of some of the other topical mechanisms. Capsaicin, for example, has received substantial interest over the past several years given increased research into the transient receptor potential (TRP) family of receptors and the role they play in pain and thermoregulation.^18,19 Capsaicin specifically antagonizes transient receptor potential vanilloid-1 (TRPV-1) receptors, while menthol has been shown to antagonize transient receptor potential melastatin-8 (TRPM-8) receptors.^18,19

Both receptors are expressed on primary nociceptive afferents (small A-delta and C-nerve fibers) and have been shown to potentiate pain signaling.^18,19 Thus, their inhibition allows for neurotransmitter depletion (including substance P) and reductions in pain signaling. Menthol has also been shown to block peripheral inflammatory responses and release of vasoactive neuropeptides.²⁰ Lidocaine, on the other hand, inhibits voltage-gated sodium channels in sensory neurons, and thus produces local anesthetic effects.⁸

Further, there are some products that have garnered enough evidence to achieve FDA approval, including the Salonpas pain relief patch (available OTC), diclofenac gel (available OTC), and capsaicin 8% pain patch (available via prescription).

The specific Salonpas Pain Relief Patch has garnered FDA approval for mild to moderate acute aches and pains of muscles and joints contains 10% methyl salicylate and 3% l-menthol. It achieved approval primarily from the randomized, double-blind, parallel-group, placebo-controlled study by Higashi et al who found that a single 8-hour application of the patch provided significant relief of pain associated with mild to moderate muscle strain in adult patients compared to placebo.²¹

The prescription capsaicin 8% patch is dosed at a much higher concentration than OTC capsaicin products, however the higher concentration has demonstrated analgesia that lasts for several weeks to months, possibly secondary to long-term loss of function of TRPV-1 receptor expression.^18,19 It is approved for both post-herpetic neuralgia and diabetic peripheral neuropathy under medically supervised settings.

NSAIDs

Perhaps one of the most overutilized classes of analgesic medications are nonsteroidal anti-inflammatory drugs (NSAIDs). The primary anti-inflammatory mechanism of these medications involves inhibition of the cyclooxygenase (COX) enzymes 1 and 2, which subsequently blocks the conversion of arachidonic acid into various prostaglandins depending on the specific tissue.²²

Traditionally, NSAIDs have been used to treat pains that are primarily inflammatory and nociceptive in nature (with efficacy), however, there has been some recent preclinical evidence suggesting potential associations between acute NSAID use and potentiation of chronic pain from acute pain etiologies.²³ Thus, despite the longevity that this class has had over the past several decades, its future use has yet to be determined and could be an important consideration.

What is often overlooked with NSAID therapy is their side effect profile. Traditional risks of all NSAID types (independent of COX-2 selectivity) include renal toxicity, cardiovascular toxicity, and gastrointestinal bleeding. There are a variety of specific mechanisms that NSAIDs possess that induce kidney injury including reducing overall renal plasma flow (through reduction in vasodilatory prostaglandins), increasing sodium retention and edema, increasing presence of inflammatory cell infiltrate in the interstitium, causing acute interstitial nephritis (AIN), and potentiating renal papillary necrosis.^24-26

All these medications elevate blood pressure through reduction of vasodilatory prostaglandins in smooth muscle and can selectively reduce prostaglandin I2 (as opposed to thromboxane A2), leading to pro-platelet aggregation. This selectivity seems to be more associated with COX-2 selective inhibitors, which is why COX-2 selective NSAIDs have traditionally been recognized to carry greater cardiovascular risk; although all NSAIDs carry some, and the disparity is not as substantial as once thought.^26-29

Therefore, careful evaluation of a patient’s baseline demographics is fundamental in determining overall renal, cardiovascular, and bleeding risk when assessing for NSAID use.³⁰ In general, using lower doses, for shorter periods of time can minimize some of these underlying risks.

Gabapentinoids

The gabapentinoids, gabapentin and pregabalin, are anticonvulsant medications that have gained considerable favor in the treatment of pain over the past decade. This has been evidenced by a substantial uptick of prescribing of both drugs over this time period, almost inversing the decline in opioid prescribing.³¹

They primarily work by modulating the alpha-2-delta subunit of voltage-gated calcium channels throughout the central nervous system, which ultimately reduces excitatory neurotransmitter release (glutamate, etc.), thus helping stabilize neuronal membrane potentials.³² All this activity allows for predominantly neuropathic pain benefits. However, because this class of medication is often misunderstood, combined with a growing fear of prescribing conventional analgesics, they are increasingly overprescribed for inappropriate patients and pain conditions, usually under the impression that they can benefit anyone suffering from pain.³¹ The evidence available shows that these medications can effectively treat many neuropathic pain conditions, as opposed to pain that is nociceptive or inflammatory in nature.

It is important to note that gabapentinoids are associated with several well-known side effects including somnolence, cognitive dysfunction, lower extremity edema, and respiratory depression, among others. The one side effect that has garnered substantial concern over the past years is the rising rates of misuse/abuse of the medication and potential for addiction.

Interestingly, despite several reports alleging this developing “gabapentinoid abuse” crisis, there is little consistent data available describing the incidence and prevalence of such misuse or abuse (terms that are generally broad and ill-defined at baseline).^33-35 Further, from an addiction pathology perspective, gabapentinoids have not been shown to produce dopaminergic activity within the nucleus accumbens,³² an important facet within the addiction cascade. However, they have been shown to interact with NMDA receptors (especially at higher doses), thus some of their “addiction potential” may stem from these underlying interactions.³²

Despite all of this, gabapentinoids appear to be misused more as a function of enhancing the hedonic effects of opioids, as well as a means to ameliorate opioid withdrawal symptoms. Thus, monitoring, and appropriate patient and therapeutic selection, is crucial in optimizing the benefit and maximizing the safety involving these medications.

SNRIs and Tricyclic Antidepressants

Antidepressants comprise another commonly prescribed class of medication that has traditionally been used to treat different types of pain, though a class that continues to experience controversy to this day. The specific antidepressants that produce analgesic effects are the selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs), as both types primarily exert their effects by increasing synaptic serotonin and norepinephrine concentrations, with the primary analgesic mediator being norepinephrine.^36,37 The primary difference between SNRIs and TCAs is their selectivity toward the norepinephrine and serotonin reuptake transporters (NERT and SERT, respectively).

Interestingly, while the role these medications play in reducing neuropathic types of pain by stabilizing neuronal membrane potentials has been historically recognized, there is also evidence that activation of noradrenergic activity throughout the descending pain pathways (dorsal horn, dorsal root ganglion, etc.) can inhibit descending pain signals, thus allowing for potential benefit for nociceptive types of pain.^38-40

Perhaps the most used of these medications include the SNRIs duloxetine and venlafaxine, and the TCAs amitriptyline and nortriptyline (though many others are commercially available).

Birkinshaw et al published one of the largest comprehensive meta-analyses on these drugs in 2023.⁴¹ The review included 176 total studies assessing antidepressant efficacy in the treatment of different chronic pain conditions. The standard conclusion drawn was that their evidence showed that duloxetine was associated with a “small to moderate effect” for substantial pain relief and reducing continuous pain intensity, whereas milnacipran (another SNRI) was associated with a “small effect” on reducing pain intensity scores (both with moderate certainty of evidence).⁴¹ Although not mentioned in the conclusion, several other antidepressants showed clinically significant efficacy regarding specific data points (imipramine, venlafaxine, and desvenlafaxine). Not all antidepressants were included in every efficacy outcome measure evaluated either.

The side effect profile of these types of antidepressants comes down to their selectivity. TCAs, in general, have much lower selectivity toward just SERT and NERT transporters and have additional activity at histaminergic, alpha-1-adrenergic, muscarinic, and cholinergic receptors, thus are usually associated with greater degrees of anticholinergic, orthostatic, cardio-electroconductivity type side effects.⁴⁰ These greatly limit their use, especially in older populations or those with underlying cardiac conductivity issues. SNRIs are extremely selective toward NERTs and SERTs, thus are usually associated with lower degrees of side effects.⁴⁰

While all these antidepressants can increase risk of serotonin-related side effects – ie, bleeding and cardiovascular problems (increases heart rate and blood pressure) – it is important to note that selectivities of various TCAs and SNRIs to NERT compared to SERT can differ. For example, milnacipran and desvenlafaxine have more favorable NERT to SERT binding affinities compared to duloxetine and venlafaxine.⁴⁰ This may cause differences to the overall benefit and side effect profile when considering different SNRIs.

When Should Patients be Referred Out?

Having several different medication modalities to choose from is critically important when treating patients with chronic pain, however, so is understanding when to refer the patient out. Several factors need to be considered when assessing whether to refer out. For those fortunate enough to be parts of larger health systems, there may be specific access to multimodal pain management specialists. Thus, for some clinicians, it may be much easier to refer patients out than others. Still, it is the authors’ experience that the majority of patients prefer that we, in primary care, provide the bulk of their pain management, especially when it comes to medication prescribing.

Some of the most common reasons we would refer a patient to a pain specialist, rheumatologist, or other specialty:

• Their pain is not improving.

• We are unsure about the diagnosis.

• We think that they may be a candidate for surgery or procedure (joint replacement, spinal cord stimulation, injection).

• They have a primary rheumatologic diagnosis (lupus, RA).

• They have an underlying comorbidity that is not maximally managed (psychiatric, diabetic) that may be significantly contributing to the primary pain.

• They have comorbid substance use disorder (primary or discovered during treatment).

Conclusion

Understanding the most common medication modalities used to treat different types of pain is essential in any setting, but especially in primary care. With the growing pressures of managing a complex patient population coupled with the underpinnings of the overdose and opioid prescribing crisis, pain management has fallen on the shoulders of those in community settings.

By expanding education around pain management and the various modalities available, clinicians can arm themselves with tools to properly, appropriately, and effectively care for their patients with pain.

Disclosures: Dr. Bettinger consults for Hisamitsu America Inc.