What pain killers could replace opioids? Exploring alternatives for safer pain management

October 8, 2025 •

4 min read

An estimated 100 million Americans suffer from chronic pain, leading to a massive demand for effective treatments. But what pain killers could replace opioids to mitigate the risks of addiction and overdose associated with traditional narcotics? Recent advancements offer a range of non-opioid options, from repurposed medications to innovative new drugs.

Quick Summary

This article explores a variety of pharmacological and non-pharmacological alternatives to opioids. It covers new FDA-approved drugs, repurposed medications, and interventional therapies for both acute and chronic pain management, detailing their mechanisms, efficacy, and side effect profiles.

Key Points

Novel Analgesics: The FDA has recently approved Journavx (suzetrigine), a new non-opioid drug that blocks pain signals by targeting specific sodium channels in the peripheral nervous system.
Multimodal Approach: Effective pain management often involves combining pharmacological treatments, like NSAIDs and repurposed medications, with non-pharmacological therapies such as physical therapy and mind-body practices.
Repurposed Medications: Antidepressants (SNRIs, TCAs) and anticonvulsants (gabapentin, pregabalin) are widely used to treat chronic neuropathic (nerve) pain.
Interventional Procedures: For chronic or intractable pain, options like spinal cord stimulation, radiofrequency ablation, and nerve blocks can offer significant, localized relief.
Cannabinoid Efficacy: While evidence is still limited and needs more research, some studies suggest potential benefits of cannabinoids like CBD for certain types of chronic pain, especially neuropathic pain.
Topical Treatments: Creams and patches containing analgesics like lidocaine, NSAIDs, or capsaicin provide targeted relief for localized pain, minimizing systemic side effects.
Personalized Treatment: A tailored approach, guided by a healthcare provider, is critical for selecting the safest and most effective alternatives based on a patient's specific type of pain and health profile.

The Shifting Landscape of Pain Management

The opioid crisis has highlighted the urgent need for safer, non-addictive methods of pain relief. For many common types of acute and chronic pain, non-opioid therapies are proving to be as effective as—or even more effective than—opioids. A multimodal approach, which combines medications with non-pharmacological treatments, is now considered the best practice for managing persistent pain and improving a patient's overall quality of life. The Centers for Disease Control and Prevention (CDC) provides extensive guidance on these non-opioid options. A tailored strategy, guided by a patient-centered approach, is essential to avoiding the risks associated with long-term opioid use, such as dependence, addiction, and overdose.

Pharmacological Alternatives to Opioids

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Acetaminophen

For mild to moderate pain, over-the-counter and prescription nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen, and aspirin are common alternatives. They work by inhibiting enzymes called cyclooxygenase (COX), which reduces inflammation, swelling, and pain. However, long-term use is associated with gastrointestinal issues, and there are cardiovascular risks, particularly for those with pre-existing heart conditions. Acetaminophen (Tylenol) is another widely used pain reliever that works centrally to alter pain perception without reducing inflammation. Excessive dosing of acetaminophen can lead to liver damage, so it's crucial to follow instructions carefully. For certain conditions, such as dental pain, a combination of ibuprofen and acetaminophen has been shown to be more effective than opioids.

Novel Non-Opioid Drugs

Significant advancements are being made in the development of new, non-addictive painkillers. In January 2025, the FDA approved Journavx (suzetrigine), the first new non-opioid painkiller in decades, for moderate to severe acute pain. This drug works by targeting specific pain-signaling sodium channels (Nav1.8) in the peripheral nervous system before signals reach the brain, avoiding the addictive pathways targeted by opioids. Other drugs targeting the Nav1.8 channel are also in development, such as LTG-001. Other emerging therapies include nerve growth factor (NGF) inhibitors for osteoarthritis and chronic back pain, and GABAA receptor modulators for neuropathic pain.

Repurposed Medications: Antidepressants and Anticonvulsants

Some existing medications, originally developed for other conditions, are highly effective for managing specific types of chronic pain. Antidepressants, particularly serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine and tricyclic antidepressants (TCAs) like amitriptyline, are often used to manage chronic neuropathic pain by augmenting the brain's descending inhibitory pain pathways. Anticonvulsants, such as gabapentin and pregabalin, also play a key role, especially for nerve pain conditions like diabetic neuropathy and postherpetic neuralgia. These medications inhibit voltage-gated calcium channels, which helps reduce the perception of nerve pain.

Topical Analgesics

For localized pain, topical treatments can provide targeted relief without the systemic side effects of oral medications. These include creams, gels, and patches containing:

NSAIDs: For musculoskeletal pain.
Lidocaine: A local anesthetic that numbs the area, used particularly for nerve pain.
Capsaicin: A compound from chili peppers that works by depleting a neurotransmitter (Substance P) that transmits pain signals.

Cannabinoid-Based Therapies

Interest in cannabis and its derivatives, particularly cannabidiol (CBD) and tetrahydrocannabinol (THC), for pain management has grown. While research is still emerging, cannabinoids are believed to interact with the body's endocannabinoid system to influence pain perception. Some studies show potential benefits for specific conditions like neuropathic pain, but evidence for broad use is limited, and more research is needed to determine long-term efficacy and safety, particularly due to the lack of consistent product regulation.

Non-Pharmacological and Interventional Treatments

Beyond medication, a host of therapies can effectively manage pain and reduce the need for pills. Many can be used alone or in combination with medications for a multimodal strategy.

Physical and Occupational Therapy: Therapeutic exercise, aquatic therapy, and stretching improve strength, mobility, and function, which can significantly reduce chronic pain.
Mind-Body Practices: Techniques such as acupuncture, yoga, tai chi, and mindfulness-based stress reduction can help manage the physical and emotional aspects of pain by relaxing muscles and improving the mind's response to pain signals.
Behavioral Therapy: Cognitive-behavioral therapy (CBT) helps patients reframe negative thought patterns and develop coping skills for chronic pain.
Neuromodulation and Nerve Blocks: Advanced techniques can interrupt pain signals using technology or targeted injections.
- Spinal Cord Stimulation (SCS): Uses a small, implanted device to deliver electrical pulses to the spinal cord, replacing painful sensations with a tingling feeling. Newer systems offer paresthesia-free options.
- Radiofrequency Ablation (RFA): Uses radio waves to heat and burn a nerve responsible for pain signals, providing relief for up to a year.
- Injections and Nerve Blocks: Injections of local anesthetics or steroids near nerves or joints can provide significant, often temporary, relief.
- Transcutaneous Electrical Nerve Stimulation (TENS): Uses low-voltage electrical current via electrodes placed on the skin to interrupt nerve signals.

Comparison of Key Non-Opioid Options


Treatment Class	Typical Use Cases	Efficacy	Addiction Potential	Key Side Effects
NSAIDs	Mild to moderate pain, musculoskeletal conditions, inflammation	Varies by condition; very effective for inflammation-related pain.	Low (non-addictive)	Gastrointestinal issues (bleeding, ulcers), kidney problems, cardiovascular risk.
Anticonvulsants	Chronic neuropathic pain (nerve damage, neuropathy).	Modest to good for specific nerve pain conditions.	Low (non-addictive)	Sedation, dizziness, blurred vision, fatigue.
Neuromodulation (SCS)	Intractable chronic pain, failed back surgery syndrome.	Significant pain relief for many, with long-lasting effects.	None	Procedure-related risks, infection, device issues.

Conclusion

The range of effective and non-addictive options for pain management continues to grow, offering powerful alternatives to opioids. From established over-the-counter medications and repurposed drugs to cutting-edge novel therapeutics and advanced interventional procedures, patients now have a wider array of tools to find relief. Combining pharmacologic treatments with non-pharmacological approaches like physical therapy, mind-body practices, and behavioral therapy allows for a truly multimodal and patient-centered strategy. The future of pain management focuses on personalized, safe, and effective solutions that minimize the risks associated with the opioid epidemic.

For more information on non-opioid therapies, visit the CDC's comprehensive guide on the topic: Nonopioid Therapies for Pain Management - CDC.

Frequently Asked Questions

There is no single "best" non-opioid painkiller, as effectiveness varies depending on the type and severity of pain. For mild to moderate pain, many find NSAIDs like ibuprofen or acetaminophen effective. For specific conditions, such as nerve pain, other medications or therapies may be more suitable.

Yes. In early 2025, the FDA approved Journavx (suzetrigine) for treating moderate to severe acute pain. This is the first novel non-opioid drug in its class approved in decades and works by blocking pain signals at sodium channels.

Yes, some antidepressants (SNRIs and TCAs) and anticonvulsants (gabapentin, pregabalin) are used off-label for chronic neuropathic pain. They can help modulate pain signals and are often prescribed for nerve pain conditions.

Non-drug options include physical therapy, acupuncture, massage, mindfulness meditation, and cognitive-behavioral therapy (CBT). For chronic pain, interventional procedures like spinal cord stimulation and radiofrequency ablation are also available.

Topical analgesics like lidocaine patches, capsaicin creams, and NSAID gels provide localized, targeted pain relief directly at the source. This can be effective for muscle aches or nerve pain and reduces the systemic side effects and addiction risk of oral medications.

Limited evidence suggests that cannabis and cannabinoids like CBD may provide a small benefit for some types of chronic pain, particularly neuropathic pain. However, more research is needed, and its use is often limited by inconsistent regulation and potential side effects.

Long-term use of NSAIDs can lead to serious side effects, including gastrointestinal issues (bleeding, ulcers), kidney problems, and an increased risk of cardiovascular events like heart attack and stroke.

A multimodal approach combines multiple strategies for pain relief, including a mix of pharmacological (non-opioid medications) and non-pharmacological treatments (physical therapy, psychological support, interventional procedures). This comprehensive strategy is tailored to the patient and reduces reliance on a single treatment type, such as opioids.