A Clinical Approach for Pain Relief in Pain Pharmacology

Understanding pain pharmacology in a clinical approach is crucial for effective treatment and optimal patient outcomes in pain management.

Abstract

Welcome to our educational series on innovative and comprehensive pain management strategies. In this post, I will guide you through the intricate world of pharmacological pain management from my perspective as a practitioner dedicated to integrative care. With my credentials as a Doctor of Chiropractic (DC), Advanced Practice Registered Nurse (APRN), Family Nurse Practitioner (FNP-BC), Certified Functional Medicine Practitioner (CFMP, IFMCP), and certifications in anti-aging, regenerative, and functional medicine (ATN) and clinical services and technology (CCST), I am dedicated to bridging the gap between various healthcare disciplines to offer you the most effective, evidence-based care possible.

This educational article offers a comprehensive exploration of contemporary pain management strategies. It begins by setting the stage for successful care, emphasizing the management of patient expectations and moving beyond the simple 0-10 pain scale to focus on functional goals. We will then explore foundational analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), dissecting their mechanisms, efficacy, and significant systemic risks, including gastrointestinal and cardiovascular side effects. The discussion will demystify the pain pathway, explaining the physiological processes of transduction, transmission, and perception, before exploring the often-underutilized role of topical agents (diclofenac, lidocaine, capsaicin).

Following this, the article will provide an in-depth analysis of neuropathic agents, focusing on anticonvulsants such as gabapentin and pregabalin, explaining their function as “membrane stabilizers” and discussing the latest research on their cardiovascular risks. We will then transition to the role of antidepressants in pain, clarifying how they work independently of mood and how to manage risks like serotonin syndrome. We will also discuss benzodiazepines, muscle relaxants, and the critical role of the cytochrome P450 enzyme system in opioid metabolism. Finally, we will explore innovative options like low-dose naltrexone (LDN) and the new non-opioid analgesic suzetrigine.

Throughout the post, we will integrate clinical observations and emphasize how our multidisciplinary team at Injury Medical Clinic PA in El Paso, Texas, combines chiropractic care, medical oversight from our Medical Director Dr. Maria Guadalupe Cardenas, MD, functional medicine, and rehabilitation to create personalized, effective, and evidence-based treatment plans for acute and chronic pain.

Our Collaborative Care Model: A Fusion of Expertise

At Injury Medical Clinic PA (also known as Mission Plaza Injury Medical Clinic) in El Paso, Texas, we have cultivated a unique environment where different medical disciplines converge for the patient’s benefit. I, Dr. Alex Jimenez, bring my expertise as a Doctor of Chiropractic (DC), Advanced Practice Registered Nurse (APRN), Board-Certified Family Nurse Practitioner (FNP-BC), Certified Functional Medicine Practitioner (CFMP, IFMCP), and specialist in various advanced therapies (ATN, CCST). My role is to view the patient through a holistic lens, focusing on biomechanics, nervous system function, and the underlying root causes of disease. Over decades in integrative practice, I have seen that pain management succeeds when we build a scaffold of physiology-informed interventions and a team that can address the neural, musculoskeletal, inflammatory, and psychosocial dimensions of pain.

The expertise of Dr. Maria Guadalupe Cardenas, MD, our esteemed Medical Director and Collaborative Physician, powerfully complements this approach. With over 40 years of experience as a Board-Certified Internist (NPI #1164426749, Texas MD License #J2933), Dr. Cardenas provides invaluable medical oversight. This multidisciplinary setup is a cornerstone of modern integrative and injury care. It allows us to seamlessly blend the structural and neurological focus of chiropractic care with the diagnostic and pharmacological rigor of internal medicine. Her leadership in the clinic ensures appropriate medical screening for cardiovascular, renal, hepatic, endocrine, and autoimmune conditions, as well as safe medication selection and monitoring.

Together, our team integrates:

• Chiropractic Care & Neuromusculoskeletal Assessment (My Role): To restore spinal alignment, improve nervous system communication, reduce biomechanical stress, and modulate peripheral nociception.
• Medical Oversight (Dr. Cardenas): For comprehensive medical evaluation, prescription management, addressing complex comorbidities, and ensuring diagnostic precision.
• Functional Medicine: To investigate and address root causes related to diet, lifestyle, genetics, and environment, targeting biochemical and lifestyle drivers of pain.
• Personal Injury Care & Rehabilitation: To guide patients through recovery after accidents with targeted physical therapies, documentation, and support.
• Pharmacological Management: Judiciously using medications when necessary, as part of a broader, more comprehensive strategy.

This collaborative model ensures that when medications are deemed necessary, their use is part of a larger, synergistic plan aimed at restoring function and long-term wellness, not just masking pain. This post represents how I communicate these ideas to patients, families, and professionals—grounded in the latest research, tempered by clinical experience, and structured around safety, function, and patient values.

Setting the Stage: The Importance of Patient Expectations

Before we delve into the specifics of pharmacology, it’s crucial to address a foundational element of successful care: managing patient expectations. In my 25 years in healthcare, first as a nurse and for the last 19 as a nurse practitioner and chiropractor, I’ve learned that pain management is a process, not a pill. This isn’t just a catchy phrase; it’s a clinical reality.

The perception of pain and the expectation of relief are profoundly intertwined. A fascinating study revealed a startling insight: patients who experienced anything less than 100% pain relief often equated this outcome with their providers withholding care. This all-or-nothing mindset is not only a disservice to the provider but, more importantly, a significant barrier to the patient’s own progress. It sets an unrealistic standard that is rarely, if ever, achieved in chronic pain management.

Understanding Clinical Significance

In the world of clinical research, the benchmark for a “successful” pain intervention is a 30% to 60% improvement. At first glance, this might seem underwhelming. If you were to purchase a service and were told you would only receive 30% of the promised benefit, you would rightly feel skeptical about your return on investment. This is precisely why a singular approach is so often doomed to fail. We understand this, which is why we champion a multimodal strategy.

The power of integrative care lies in synergy. If we can achieve:

• 30% relief from a specific medication…
• 20% improvement from targeted chiropractic adjustments…
• 25% reduction in pain from an anti-inflammatory diet and functional medicine protocols…
• 15% functional gain from physical rehabilitation…

Suddenly, we are “chipping away” at the pain from multiple angles, and the cumulative effect can be profound and life-changing.

Moving Beyond the 0-10 Pain Scale

To effectively track this progress, we must move beyond the ubiquitous 0-10 pain scale. While it’s a required metric in many clinical settings, it is a blunt and often misleading instrument. It fails to capture the rich context of a person’s life and function.

A patient’s “10″ on the pain scale can mean two completely different things:

1. A “10” while lying motionless on the couch, unable to engage with life.
2. A “10” after spending a joyful afternoon walking through the mall with their granddaughter, an activity that was impossible a month ago.

The second “10” is a victory. It represents a massive improvement in function and quality of life. This is what we are truly aiming for.

To capture this, we utilize more comprehensive tools and encourage patients to identify their own functional goals. The Brief Pain Inventory (BPI), a seven-question scale, is an excellent tool that focuses on how pain interferes with mood, mobility, work, and social relationships. Alternatively, we work with patients to define their own personal metrics for success:

• “I want to be able to sleep through the night without waking up from pain.”
• “I want to walk my dog for 20 minutes without needing to stop.”
• “I want to sit through a full dinner with friends without constantly shifting in my seat.”

By documenting and tracking these functional goals, both the patient and our team become invested in a shared, meaningful journey toward recovery. This documentation is what truly helps us measure whether our comprehensive plan is working.

Foundations: Understanding the Pain Pathway and Physiology

To effectively manage pain, it is crucial first to understand how it works. I often explain this process to my patients as a journey—a signal that travels from the point of injury all the way to the brain. When we appreciate each step of this journey, it becomes clear that we have multiple opportunities to intervene and provide relief.

The pain process can be broken down into key stages: transduction, transmission, modulation, and perception. Let’s use a simple example: imagine you accidentally smash your hand in a door.

1. Transduction: This is the initial step, where the injury occurs. The physical damage to your tissues triggers the release of a cocktail of inflammatory and chemical mediators right at the site of injury. These include prostaglandins, histamine, bradykinin, and serotonin. These chemicals don’t just cause inflammation; they also activate specialized nerve endings called nociceptors (A-delta and C fibers). These nociceptors are your body’s “pain receptors,” and their job is to convert the physical or chemical stimulus into an electrical signal, or nerve impulse.
2. Transmission: Once the nociceptor is activated, this electrical impulse begins its journey. It travels from your hand, up your arm, and to the spinal cord. Specifically, it arrives at a region in the spinal cord called the dorsal horn. From there, neurotransmitters like glutamate and substance P amplify signals, and the information travels via the spinothalamic tract and other routes to the brain.
3. Modulation: This is where the brain exerts top-down control. Through pathways originating in areas like the periaqueductal gray and locus coeruleus, the brain releases its own pain-dampening neurotransmitters, such as serotonin and norepinephrine, to inhibit incoming pain signals at the spinal cord level. This is known as the descending inhibitory pathway.
4. Perception: Finally, the signal reaches various brain regions, such as the thalamus, insula, and cortex. The brain processes this information, interprets it as pain, and generates the conscious experience of hurting. This is the moment you feel the pain in your hand.

A key concept in chronic pain is central sensitization. Repetitive or intense pain signals can remodel the synapses in the spinal cord, making the nervous system hyper-responsive. This lowers pain thresholds, meaning that normally non-painful stimuli can become painful. Antidepressants, for example, help pain by enhancing the descending inhibitory pathway, while certain anticonvulsants work by reducing the hyperexcitability of nerves involved in transmission. Understanding this roadmap allows us to select targeted therapies.

Foundational Pharmacology: Acetaminophen and NSAIDs. We’ll begin our pharmacological overview with two of the most common and widely available analgesics: acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs).

Acetaminophen (Tylenol)

What is truly mind-blowing about acetaminophen is that after decades of use, its precise mechanism of action is still not fully understood. It’s believed to work primarily within the central nervous system to inhibit pain signals, but the exact pathways remain a subject of research.

What we do know with certainty is its potential for harm. Acetaminophen carries a significant risk of hepatotoxicity (liver damage) at doses exceeding four grams (4,000 mg) per 24 hours. This is a critical piece of information that we must relentlessly communicate to our patients.

The statistics are sobering:

• Approximately 30,000 patients are hospitalized annually in the United States for acetaminophen-related liver toxicity.
• Alarmingly, half of all acetaminophen overdoses are unintentional.

This happens because acetaminophen is a hidden ingredient in hundreds of over-the-counter products, including cold and flu remedies, sinus medications, and combination pain relievers. The “Know Your Dose” campaign is a valuable public health initiative that aims to educate consumers about these hidden dangers. In our clinic, we make it a point to review every medication and supplement a patient is taking to prevent such accidental overdoses. While large-scale studies have shown limited evidence for its efficacy in chronic low back pain, I have seen patients with severe spinal issues who find remarkable relief from a simple regimen of two regular-strength Tylenol tablets twice a day. Our role is to find the middle ground through education and careful monitoring, ensuring that if it is used, it’s used safely.

A Deeper Look at Anti-Inflammatories (NSAIDs)

We now transition to non-steroidal anti-inflammatory drugs (NSAIDs). Patients often turn to NSAIDs like ibuprofen (Advil, Motrin) or naproxen (Aleve), believing them to be a universally safe alternative. While they can be incredibly effective, they carry significant risks that are often underestimated.

Efficacy and Individual Response

No single NSAID has been proven to be universally more efficacious than another. Individuals can have vastly different responses. Someone might fail trials of ibuprofen, naproxen, and meloxicam, only to find relief with diclofenac. This is because NSAIDs belong to different chemical classes. A true therapeutic trial requires consistent dosing for at least four days.

The Systemic Nature of GI Side Effects

One of the most common misconceptions about NSAIDs is how they cause gastrointestinal (GI) issues. The primary cause of NSAID-induced GI damage is systemic, not localized. Here’s why:

1. NSAIDs work by inhibiting cyclooxygenase (COX) enzymes, which produce prostaglandins.
2. Prostaglandins promote inflammation, pain, and fever.
3. However, certain prostaglandins also play a vital gastro-protective role, maintaining the protective mucus layer of the stomach and intestines.
4. When NSAIDs systemically block all prostaglandin production, they strip away this protective lining, leaving the GI tract vulnerable to damage, ulceration, and bleeding.

A study on healthy volunteers taking 800 mg of ibuprofen three times a day found that a GI bleed could occur within just three to five days.

Key Considerations and Drug Interactions

• Anticoagulants: We generally avoid combining most NSAIDs with blood thinners because NSAIDs also inhibit platelet function, dramatically increasing bleeding risk. The notable exception is celecoxib (Celebrex), a COX-2 selective inhibitor.
• Low-Dose Aspirin: Combining daily aspirin with a traditional NSAID can double the risk of a significant GI bleed.
• Proton Pump Inhibitors (PPIs): Medications like omeprazole (Prilosec) are often co-prescribed. However, PPIs only protect against ulceration in the stomach; they offer no protection for the small intestine.
• Celecoxib (Celebrex), being a COX-2 selective NSAID, targets the inflammatory COX-2 enzyme more specifically while largely sparing the gut-protective COX-1 enzyme, giving it a better GI safety profile.

The Cardiovascular Risks of NSAIDs

Beyond the gut, the cardiovascular risks associated with NSAIDs are a major concern. All NSAIDs, with the potential exception of naproxen, carry an increased risk of heart attack and stroke. Celecoxib (Celebrex), while safer for the gut, does not offer any advantage in terms of cardiovascular risk.

The danger is amplified in patients who have already had a heart attack (post-MI). A study showed that adding an NSAID to a post-MI patient’s regimen doubled the risk of bleeding, observable in as little as three days of NSAID use. Perhaps the most startling finding is that taking an oral NSAID during a respiratory infection could increase the risk of a first-time heart attack threefold in otherwise healthy individuals.

Navigating the Different Classes of NSAIDs

Knowing the different chemical families of NSAIDs can guide a more strategic approach. If a patient fails a trial with a drug from one class, it’s logical to try an agent from a different class.

• Propionic Acids: Ibuprofen, Naproxen
• Acetic Acids: Diclofenac, Indomethacin
• Oxicams: Meloxicam, Piroxicam
• COX-2 Selective Inhibitors: Celecoxib
• Fenamates: Meclofenamate

In my practice, I frequently use meloxicam. If a patient doesn’t find it effective, I might purposefully select one from the acetic acid group, like diclofenac, to see if the different chemical structure yields a better result.

Balancing Body and Metabolism- Video

The Overlooked Power of Topical Agents

Given the systemic risks of oral medications, topical agents represent a highly valuable and often underutilized tool. By applying medication directly to the site of pain, we achieve high local concentrations of the drug while minimizing systemic absorption and side effects. This approach is particularly beneficial for localized pain, elderly patients, and those with GI or cardiovascular comorbidities.

From a chiropractic and rehabilitation perspective, topical agents are a perfect adjunct to our hands-on therapies. Applying a topical before or after manual therapy can reduce local inflammation and pain, making the treatment more comfortable and effective.

Topical NSAIDs: Diclofenac Gel (Voltaren)

Diclofenac gel (Voltaren) works by inhibiting COX enzymes directly at the site of inflammation. Research has shown its efficacy to be comparable to that of oral NSAIDs for conditions like osteoarthritis, but with a significantly better risk profile. The American College of Rheumatology strongly recommends topical NSAIDs for patients over 75 with knee or hand osteoarthritis. The diclofenac patch (Flector) is another excellent option for acute strains and sprains.

Topical Anesthetics: The Role of Lidocaine

The lidocaine patch is particularly effective for neuropathic pain. It works by blocking sodium channels on peripheral nociceptors, stabilizing the nerve membrane and preventing it from transmitting pain signals. Its efficacy is well-documented in postherpetic neuralgia (PHN), the debilitating nerve pain after a shingles outbreak. One landmark study showed a 65% improvement in pain and a 77% improvement in quality of life at just one week. The patches are worn for 12 hours on, 12 hours off to prevent skin irritation.

Capsaicin: Harnessing the Power of Chili Peppers

Capsaicin targets the TRPV1 receptor on peripheral nerve endings. It initially causes a burning sensation as it stimulates the nerve and releases Substance P. However, with repeated application, it depletes the nerve’s stores of Substance P and desensitizes the nerve ending, effectively “burning out” its ability to transmit pain signals. The high-concentration Qutenza (8% capsaicin) patch can provide pain relief for up to three months from a single clinical application and is effective for diabetic peripheral neuropathy and PHN.

Off-Label and Compounded Topical Agents

• Topical Clonidine: An alpha-2 adrenergic agonist that can be compounded into a gel to help modulate pain in conditions like Complex Regional Pain Syndrome (CRPS).
• Magic Mouthwash: A term for various compounded oral rinses used to treat painful mouth sores (mucositis), often seen in cancer patients. Formulations typically include a local anesthetic (lidocaine), an antacid (Maalox), and an antihistamine. I find this incredibly helpful for my patients with oral ulcerations.

Neuropathic Agents: Stabilizing Overexcited Nerves

When pain becomes chronic or involves nerve damage, we often turn to neuropathic agents. The key concept is that of a “membrane stabilizer.” When a nerve is injured or chronically irritated, it can become hyperexcitable, firing pain signals excessively. These medications work directly on the nerve to calm this hyperexcitability and restore normal function.

Gabapentin (Neurontin) and Pregabalin (Lyrica)

Gabapentin and its successor, pregabalin, are classic membrane stabilizers. They do not directly affect the GABA system.

• Mechanism of Action: They bind to a specific subunit of voltage-gated calcium channels on presynaptic neurons. This reduces calcium influx into the nerve terminal, which in turn decreases the release of excitatory neurotransmitters like glutamate and Substance P. I explain it to patients as “turning down the volume” of the overactive nerve.
• Dosing and Titration: Start Low, Go Slow: Proper dosing is critical. We begin with a very low dose (e.g., 100 mg of gabapentin at bedtime) and gradually increase it every few days. This minimizes side effects like dizziness and drowsiness and helps us find the minimum effective dose.
• Clinical Pearls for Gabapentin:

• • It is only FDA-indicated for postherpetic neuralgia, but is widely used off-label.
  • The dose must be adjusted in patients with renal impairment.
  • Bioavailability paradoxically decreases at higher doses, leading to diminishing returns.
  • It’s associated with central sleep apnea and the rare but serious DRESS syndrome.

• Clinical Pearls for Pregabalin:

• • It has more predictable, linear pharmacokinetics than gabapentin.
  • Therapeutic benefit often plateaus above 450 mg/day, while side effects increase.

• New Cardiovascular Risk Data: A significant finding from a 2025 study showed an increased risk of five-year adverse cardiovascular events in patients with diabetic neuropathy or fibromyalgia taking these medications. This requires a thoughtful conversation with patients about long-term risks, especially those with pre-existing heart disease.

Other Anticonvulsants: What I Avoid for Pain

Not all anticonvulsants are effective for pain. Based on the evidence, I avoid using lamotrigine and topiramate (Topamax) for general chronic neuropathic or musculoskeletal pain (topiramate’s primary indication is migraine prevention). Gabapentin and pregabalin are best for neuropathic pain phenotypes and may not help purely mechanical pain.

Antidepressants for Pain: Targeting the Descending Pathway

I often use certain antidepressants for pain, and I make it clear to patients: this is about neurophysiology, not labeling their pain as “in their head.” Antidepressants, particularly Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and Tricyclic Antidepressants (TCAs), enhance the descending inhibitory pathway. By increasing levels of serotonin and norepinephrine in the spinal cord, they help the brain dampen incoming pain signals. This analgesic effect is independent of their effect on mood.

Communicating the Black Box Warning

The FDA issued a black box warning for increased suicidal thoughts/behaviors in children and adolescents taking antidepressants. I address this upfront with patients:

• In individuals older than 24, no increased risk was observed.
• The highest risk is in young adults (18–25), where motivation may increase before mood improves.
• Adults over 65 may even experience a protective effect.

This simple conversation, followed by a structured monitoring plan, helps prevent fear and misconceptions.

Serotonin Syndrome: Awareness and Diagnosis

Serotonin syndrome is a rare but serious condition caused by excessive serotonergic activity. Onset is typically within hours of a dose change. Key features include sweating, fever, agitation, tremor, and clonus (involuntary muscle contractions). We use the validated Hunter’s criteria for diagnosis, which heavily relies on the presence of clonus. Reviewing a patient’s full medication list (including tramadol, triptans, etc.) is crucial to manage serotonergic load.

Duloxetine (Cymbalta) and Other SNRIs

• Duloxetine (Cymbalta): An SNRI indicated for fibromyalgia, chronic musculoskeletal pain, and painful diabetic neuropathy. It is especially useful for chronic low back pain and osteoarthritis (OA) of the knee, offering an alternative to long-term NSAID use. We start at 30 mg daily for one week to reduce nausea, then increase to the typical 60 mg therapeutic dose.
• Milnacipran (Savella): Indicated only for fibromyalgia. It has a higher norepinephrine affinity and can cause “speedy” effects like agitation.
• Venlafaxine (Effexor): Has limited evidence for general pain but some support for painful diabetic neuropathy. I rarely select it first for pain.

Tricyclic Antidepressants (TCAs): Time-Tested Tools

TCAs like amitriptyline and nortriptyline remain powerful analgesics at low doses. Their mechanisms include serotonin/norepinephrine reuptake inhibition, sodium channel blockade, and NMDA modulation. For pain, we start low (10 mg at night) and titrate slowly up to 30-50 mg. While they have anticholinergic side effects (dry mouth, constipation), these are manageable at low doses.

Burning Mouth Syndrome: A Focused TCA Protocol

Burning mouth syndrome is a persistent oral burning sensation without visible signs, often seen in postmenopausal women. It is profoundly frustrating but treatable. My protocol involves starting nortriptyline 10 mg nightly and titrating up weekly as needed. Many patients find relief within weeks after years of suffering.

Muscle Relaxants and Benzodiazepines: A Critical Look

Muscle Relaxants: Limited Efficacy

For conditions like sciatica, the muscle relaxant class as a whole shows no significant benefit. For acute low back pain, they may offer modest improvement for one week, but the benefit quickly diminishes. The primary mechanism seems to be general central nervous system (CNS) depression (sedation) rather than a direct effect on muscle tissue.

• Diazepam (Valium): A benzodiazepine, it is not superior to other muscle relaxants and carries a high risk of dependence.
• Cyclobenzaprine (Flexeril): Chemically similar to TCAs, it can accumulate in the body due to a long half-life, leading to constant grogginess and an increased risk of falls. Caution is needed in patients with mood disorders.
• Tizanidine (Zanaflex): A central alpha-2 adrenergic agonist with a very short duration of effect. This is an advantage, as it gives the patient control to take it when needed (e.g., at bedtime) without causing all-day impairment.
• Carisoprodol (Soma): A Schedule IV controlled substance with high abuse potential. I rarely, if ever, prescribe it.
• Baclofen: Indicated for severe spasticity (e.g., from MS or spinal cord injury). Abruptly stopping long-term baclofen can be fatal, leading to seizures and high fever. This is a medical emergency, especially if an intrathecal pump fails.

The Perils of Co-Prescribing: Benzodiazepines and Opioids

Benzodiazepines are not analgesics. In fact, research shows they can antagonize the pain-relieving effects of opioids. Combining them is incredibly dangerous.

• The overdose rate is ten times higher for patients on high-dose opioids who are also taking benzodiazepines.
• Admissions to substance abuse programs for concurrent use skyrocketed by 570% over ten years.

This does not mean we should abandon patients with legitimate anxiety disorders. We must treat co-occurring pain and anxiety concurrently and with integrated, safer methods.

The Role of Integrative and Chiropractic Care

This is where the power of an integrative approach becomes clear. In our clinic, when a patient presents with chronic pain and anxiety, we don’t just reach for a prescription pad.

• Comprehensive Assessment: We start with a deep dive using functional medicine to identify biochemical imbalances, nutritional deficiencies, or inflammatory triggers.
• Chiropractic Adjustments: Spinal misalignments can interfere with nerve function and contribute to chronic stress and pain sensitivity. Gentle, precise adjustments can help restore proper nervous system function, reduce physical tension, and have a calming effect. By addressing the underlying joint dysfunction and nerve irritation that causes a muscle to spasm, we can provide lasting relief without systemic CNS depression.
• Mind-Body Therapies: We guide patients toward evidence-based techniques like mindfulness, CBT, and biofeedback to empower them to manage their own anxiety and change their relationship with pain.
• Medical Collaboration: Under Dr. Cardenas’s guidance, if anxiolytic medication is necessary, we can carefully select options with a lower risk profile and monitor the patient closely.

Innovative Therapies: LDN and a New Non-Opioid

Low-Dose Naltrexone (LDN): A Paradigm Shift

Low-dose naltrexone (LDN) is one of the most exciting therapies in functional medicine. Naltrexone in a high dose (50 mg) is used for addiction treatment. However, at a very low, compounded dose (1.5 to 4.5 mg), it works differently.

• Mechanism: LDN is believed to modulate the immune system by calming activated glial cells (microglia and astrocytes) in the CNS, reducing the production of inflammatory cytokines. This addresses the neuroinflammation that drives many chronic pain states. It also causes a brief blockade of opioid receptors, which prompts the body to upregulate its own production of endorphins.
• Clinical Applications: It must be prepared by a compounding pharmacy. A growing body of evidence supports its use for fibromyalgia, Long COVID, Crohn’s disease (with evidence of endoscopic healing), and Ehlers-Danlos Syndrome.
• Dosing: We start at 1.5 mg at bedtime and slowly titrate up to a target of 4.5 mg. It will not interfere with emergency pain relief, as a standard opioid dose will easily override its effects.

Suzetrigine (VX-548): The New Kid on the Block

Approved by the FDA in February 2025, suzetrigine is a novel non-opioid analgesic for moderate to severe acute pain.

• Mechanism: It selectively inhibits the NaV1.8 sodium channel, which is found predominantly on peripheral pain-sensing neurons. This blocks the pain signal at its source without the central side effects of opioids.
• Efficacy: In clinical trials, its efficacy was almost equal to taking 5 mg of hydrocodone twice a day. Being non-inferior without the risks of an opioid is a major achievement.
• Important Considerations:

• • Some insurance plans are requiring patients to fail a trial of hydrocodone before approving this safer drug, a counterintuitive policy.
  • It can affect the metabolism of some oral contraceptives. Patients must be counseled to use an alternative, reliable form of contraception for at least one month after finishing the medication.

Humanizing Opioid Therapy: A Responsible Approach

Opioids can be a necessary tool for select patients when other options have failed. To ground this discussion, consider two of my actual patients: Mike, a 56-year-old construction worker with bulging discs and facet arthropathy who remains functional on a low, stable dose of hydrocodone; and Sheila, an 84-year-old woman with severe adjacent segment disease who is not a surgical candidate and maintains her quality of life with an extended-release oxycodone regimen. For them, the benefits outweigh the risks.

Fundamentals of Opioid Action

Opioids work on mu, delta, and kappa receptors to modulate ascending and descending pain pathways. The mu-receptor is responsible for most analgesic effects but also for side effects like respiratory depression and opioid-induced constipation (OIC). An important clinical pearl is that opioids can stimulate antidiuretic hormone (ADH) release, causing fluid retention and reducing the efficacy of diuretic medications.

The Responsible Opioid Prescribing Checklist

Before initiating long-term opioid therapy, a systematic process is essential:

• Perform a comprehensive physical exam.
• Use a validated risk assessment tool (e.g., SOAP-R).
• Rule out “fixable” causes of pain.
• Implement a formal medication agreement (pain contract).
• Check the Prescription Drug Monitoring Program (PDMP) before every prescription.
• Meticulously document all “tried and failed” non-opioid and non-pharmacological therapies.

The Role of Genetics: Cytochrome P450 (CYP450)

The vast inter-patient variability in opioid response is often due to genetics, specifically the CYP450 enzyme system in the liver.

• Inhibitors slow down metabolism, leading to enhanced effects and toxicity at standard doses.
• Inducers speed up metabolism, causing the drug to be cleared too quickly to be effective. These patients are often unfairly labeled as “drug-seeking” when they are “ultra-rapid metabolizers.”

A crucial clinical pearl: Morphine and hydromorphone (Dilaudid) do not rely on the CYP450 system. If a patient responds poorly to oxycodone or hydrocodone but says “only morphine or Dilaudid works,” they might be right. Their genetics may dictate this response. Switching to an opioid that bypasses the problematic CYP450 pathway can be a highly effective strategy.

Buprenorphine and Methadone: Handle with Care

• Buprenorphine (Butrans, Belbuca): A partial mu-agonist with a ceiling effect on respiratory depression, making it a much safer option, especially for older people. The Butrans patch is an excellent choice for chronic pain. Critically, it is no longer recommended to stop buprenorphinebeforeo surgery.
• Methadone: A highly effective but dangerous drug if mismanaged. Its pain-relieving effect (4-6 hours) is much shorter than its plasma half-life (8-59 hours), creating a high risk of “stacking” and accidental overdose. Conversion from other opioids is complex and non-linear. My advice: If you don’t know how to use it, don’t use it.

Managing Side Effects and Ensuring Safety

Opioid-Induced Constipation (OIC)

This is a serious side effect. Do not tell patients to take bulk-forming agents like Metamucil, as this can worsen the problem. For true OIC, we use Peripherally Acting Mu-Opioid Receptor Antagonists (PAMORAs) like methylnaltrexone (Relistor) or naloxegol (Movantik). These drugs block opioid receptors in the gut without crossing the blood-brain barrier, reversing constipation without affecting pain relief.

The Life-Saving Role of Naloxone (Narcan)

Every patient on chronic opioid therapy, and every household, should have naloxone. I use the phrase: “This is for a risky drug, not a risky patient.” The mere act of prescribing naloxone has been shown to decrease overdose rates, as it raises awareness. Naloxone is now available over-the-counter. Store it somewhere easily accessible in an emergency and always call 911 after administration.

Conclusion: A Harmonized Path To Pain Relief

Integrative pain care thrives when medical oversight, chiropractic precision, functional medicine, and rehabilitation work in concert. Antidepressants, anticonvulsants, and opioids are tools—not labels—aimed at known neurophysiologic targets. We minimize risk with transparent education and structured monitoring. We maximize benefit by pairing medications with manual therapy, movement, sleep optimization, and nutrition.

At Injury Medical Clinic PA, Dr. Maria Guadalupe Cardenas and I collaborate daily to deliver this balanced, evidence-based approach. Our mission is straightforward: reduce pain, restore function, and help patients reclaim their lives with methods that make sense and work together.

As I often share in my clinical observations and frameworks on Chiropracticscientist.com and LinkedIn, patients respond best when expectations are aligned with physiology. Combining modalities like duloxetine with manual therapy often accelerates the shift from high pain reactivity to functional engagement. This diversified approach lowers side effect risk and accelerates recovery.

I am incredibly proud to be a Nurse Practitioner and a Doctor of Chiropractic, and to be part of a community dedicated to lifelong learning and patient-centered care. I hope this discussion has been valuable to you.

References

1. An, D., & Lales, A. (2023). Low-dose naltrexone for the treatment of chronic pain. US Pharmacist, 48(9), 23-27.
2. Argoff, C. E. (2020). The importance of assessing and managing expectations in patients with chronic pain. Pain and Therapy, 9(2), 433–440.
3. Argoff, C. E. (2020). The importance of peripheral mu-opioid receptor antagonists in the management of opioid-induced constipation: A review. Pain and Therapy, 9(2), 435–453.
4. Bally, M., Dendukuri, N., Rich, B., Nadeau, L., Helin-Salmivaara, A., Garbe, E., & Brophy, J. M. (2017). Risk of acute myocardial infarction with NSAIDs in real-world use: Bayesian meta-analysis of individual patient data. BMJ, 357, j1909.
5. Bhala, N., Emberson, J., Merhi, A., et al. (2013). Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials. The Lancet, 382(9894), 769–779.
6. Centers for Disease Control and Prevention. (2022). CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. MMWR Recommendations and Reports, 71(No. RR-3), 1–95.
7. Cleeland, C. S., & Ryan, K. M. (1994). Pain assessment: Global use of the Brief Pain Inventory. Annals of the Academy of Medicine, Singapore, 23(2), 129–138.
8. Derry, S., Moore, R. A., & McQuay, H. J. (2012). Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews, 2012(4), CD008040.
9. Derry, S., Wiffen, P. J., Moore, R. A., & Quinlan, J. (2015). Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews, (10).
10. Koltzenburg, M., Lundberg, L. E., & Torebjörk, H. E. (1992). Dynamic and static components of cutaneous hyperalgesia following intradermal injection of capsaicin in humans. Pain, 50(1), 5-13.
11. Larson, A. M., Polson, J., Fontana, R. J., et al. (2005). Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study. Hepatology, 42(6), 1364–1372.
12. Li, G., Aschenbrenner, D. S., & Peston, D. (2025). VX-548 (Suzetrigine): A novel selective NaV1.8 inhibitor for acute pain. American Journal of Nursing, 125(5), 22-23.
13. McLean, M. J. (2011). Gabapentin in the management of neuropathic pain. Expert Opinion on Pharmacotherapy, 12(9), 1465-1478.
14. Patten, D. K., & Griesel, D. (2023). Low-dose naltrexone: A new direction in the treatment of fibromyalgia. Journal of Clinical Rheumatology, 29(2), e45-e46.
15. Perrone, J. (2024). The complexities of pain management: A modern approach. [Presentation]. American Association of Nurse Practitioners National Conference, Nashville, TN, United States.
16. Rowbotham, M. C., Harden, N., Stacey, B., Bernstein, P., & Magnus-Miller, L. (1998). Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA, 280(21), 1837-1842.
17. Sostres, C., Gargallo, C. J., & Lanas, A. (2013). Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Research & Therapy, 15(Suppl 3), S3.
18. Tassone, D. M., Boyce, E., Guyer, J., & Nuzum, D. (2007). Pregabalin: a novel ?-aminobutyric acid analog in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clinical Therapeutics, 29(1), 26-48.
19. Webster, L. R., & Gudin, J. (2020). The role of cytochrome P450 in the metabolism of opioids. Pain Medicine, 21(Suppl_1), S4-S12.

SEO Tags: integrative pain management, Dr. Alex Jimenez, Dr. Maria Cardenas, El Paso TX, chiropractic care for pain, functional medicine pain, pharmacology, NSAIDs, acetaminophen, topical pain relief, diclofenac, lidocaine patch, capsaicin, neuropathic pain, gabapentin, pregabalin, antidepressants for pain, duloxetine for chronic pain, serotonin syndrome hunter criteria, tricyclic antidepressants, burning mouth syndrome treatment, opioids, benzodiazepines, low-dose naltrexone, LDN, muscle relaxants, suzetrigine, chronic pain, fibromyalgia, opioid-induced constipation, naloxone, Narcan, cytochrome P450, pharmacogenomics, pain management specialist, multidisciplinary clinic, back pain, sciatica, injury care, personal injury rehabilitation