Reducing Opioid Reliance: Updating Acute Pain Management With Novel Non-Opioid Analgesics

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Multimodal Analgesia and ERAS Work for Acute Pain; There’s Room for Improvement

We know that when we are talking about acute pain, especially with postoperative acute pain, multimodal analgesia and ERAS enhance recovery after surgery works for acute pain. We know that. However, we can do better, and there is room for improvement.

The problem is not necessarily efficacy. We can manage acute pain. We can throw enough opioids at it and manage it completely, but there is a cost to that.

There are non-opioid options, but each of those have limitations of their own, which we need to consider when we are looking at an overall multimodal analgesic plan.

Opioids still play a major role in the management of acute pain, but there are risks involved. Those risks do not just stop in the hospital; they also continue when we discharge patients, and especially if we discharge them with prescriptions for opioids.

Same Procedure, Different Patient.

That really comes down to the core thing that pain is an experience. It is not just one piece. It is physical, it is biological, it is psychological, it is social, it is emotional, it is energetic. It is all of these things. You may have exactly the same procedure, but yet each patient may respond to pain differently.

We think about the biopsychosocial issues that relate to it. Sometimes you can have patients who have had surgeries before with inadequately treated pain, and so there is a lot of anxiety and nervousness there. You can have patients who their experience of pain is very minimal, so it really depends on that patient.

One of the key things that I want to talk about today is that this talk today is not about opioids should not be used. That is not what we are saying. Opioids are neither good nor bad. They are just opioids. When opioids are used with appropriate patients and appropriate pain conditions, they are fantastic medications.

The key thing here is that we are looking at how do we expand our options so that we can maximize our efficacy in managing acute pain while minimizing our patients' risk. In order to do that, we need to evaluate each patient with their own unique presentation as well as the procedure in order to understand how best to manage their pain while minimizing their risk.

What Opioid-Based Analgesia Can Cost In-House

When we are talking about opioids, there are complications such as respiratory depression, postoperative nausea and vomiting, sedation, urinary retention, and ileus.

Then there are risks associated with comorbid conditions and opioids when we are talking about patients with cardiac disease or pulmonary disease with decreased lung capacity and reserve. Things like morbid obesity or obstructive sleep apnea, or patients who are also co-prescribed other CNS depressants, such as gabapentinoids, benzodiazepines, or the Z-drugs. Those can all result in significantly greater risks for respiratory depression, falls, and sedation that can occur with prescribing of opioids.

Problems With Non-Opioid Meds for Acute Pain

When we start talking about non-opioids, what are the issues with them? They have a lot of value, but we also have to be aware of the risks of using them as well. For instance, NSAIDs have an analgesic ceiling and can cause GI upset and bleeding, as well as cardiovascular issues, whereas acetaminophen has a limitation due to the potential for liver damage. While local anesthetic single-injection nerve blocks are fantastic, we run the risk of rebound pain because when those blocks wear off, they wear off like a light switch. We need to make sure that we have got pain managed before that block wears off.

With corticosteroids, they can be great, but with diabetics you run issues with hyperglycemia and endocrine problems.

When we are talking about gabapentinoids and muscle relaxers, which are often used in postoperative situations, those have CNS depressant effects which can cause sedation, dizziness, and possible dependence. There are cases of patients that develop addictions to pregabalin and gabapentin.

When the Acute Pain Toolbox Gets Tight

How do we expand the toolbox that we currently have? How do we make it better? What would be ideal in terms of that unmet need? We would want a medication that provides effective relief for moderate to severe pain. By doing so, it can reduce or eliminate the reliance on opioids. The benefit of that is we can avoid respiratory depression and sedation. If this medication does not cause any of those, that is fantastic. It would be safe to use in outside highly monitored settings; meaning we can put the patient on - send them to the floor, send them home, and we do not have to worry about monitoring them for respiratory depression. Ideally, it has no abuse potential and minimum adverse effects. All of these add up to expanding our toolbox of non-opioid therapies, as well as using what we need in order to appropriately manage pain while minimizing those risks.

From here, I am going to pass this over to Dr. Engle.

NaV-igating Acute Pain: The Rise of Selective Sodium Channel Inhibition

Dr. Mitchell P. Engle (Institute of Precision Pain Medicine): Thank you. What we are going to move on to now is the mechanisms of actions of voltage-gated sodium channels in navigating acute pain.

Pain Signaling: Where NaV Channels Enter the Story

We are going to start with some basic pain signaling here. Going over the neuroanatomy where the primary afferent neuron is actually what is initially activated through transduction when it senses thermal, mechanical, or chemical stimuli, then an action potential is generated along that primary afferent neuron. The neuron synapses in the dorsal horn of the spinal cord, ascends up the spinal cord, primarily in the spinothalamic tract, and then ends up in the primary somatosensory cortex for cortical processing.

The piece we are going to concentrate on here is that propagation event along the primary afferent neuron, particularly looking at voltage-gated sodium channels. These channels allow sodium to flux into the cells and generate the action potentials.

Pain-Relevant Sodium Channels: NaV1.7, NaV1.8, and NaV1.9

Looking at some of the different subtypes of voltage-gated sodium channels that are important for nociceptive or pain transmission, there are at least nine major voltage-gated sodium channels designated as NaV1.1 through NaV1.9. Importantly, these channels have distribution differences in their tissues. Whereas NaV1.1, NaV1.2, and NaV1.6 are located primarily in the central nervous system, NaV1.4 is primarily in the muscle. Then the heart has NaV1.5, which is a critically important feature that we will discuss later.

The peripheral nervous system has three primary voltage-gated sodium channels that are important for us, which are NaV1.7, NaV1.8, and NaV1.9. They are different from one another in the way they function.

NaV1.7 is responsible for the initiation of the active potential. It rapidly activates and inactivates.

NaV1.8 actually has slower activation and inactivation, but it stays open for a longer period of time, hence, it contributes most of the sodium influx into the neurons. Hence, it is a therapeutically very important target in treatment of pain.

NaV1.9 influences the resting membrane potential and can set the sensitivity of the cell.

If we look at those in sequence, NaV1.9 sets neuronal excitability; NaV1.7 initiates the action potential, and NaV1.8 sustains the action potential.

Historical Efforts at VGSC Inhibition

Historically, voltage-gated sodium channels have been a hot topic for research, and the reason for that is that they were early on recognized as really important in trying to manage transmission of neuronal information. Local anesthetics that we use, such as lidocaine or bupivacaine, and some antiarrhythmic drugs are actually very effective sodium channel blockers. However, they have a major problem and they lack specificity that they will block NaV1.1 all the way through NaV1.9. That leads to some of their major drawbacks, such as CNS toxicity. When you block NaV1.1 and NaV1.2, you have dizziness, seizures, and neurological deficits. Cardiac toxicity, the dreaded complication with blocking NaV1.5 leads to life-threatening arrhythmias and very difficult-to-resuscitate cardiac arrest.

The result of this is that local anesthetics are very good for localized treatment, but are very poor generally for body-wide treatment and inhibition of sodium channels.

The way to overcome this hurdle has been some isoform-selective inhibition.

Suzetrigine (VX-548)

One of the specific drugs we are going to look at is suzetrigine, also known previously as VX-548. This is a highly selective, orally bioavailable inhibitor of NaV1.8. Again, this is the sustaining voltage-gated sodium channel in the peripheral nerves.

The way that it works is that it allosterically modulates the voltage-sensitive domain of NaV1.8, and it blocks the channel in the closed state so that sodium ions cannot flow into the cell. That reduces high-frequency firing without affecting light, touch sensitivity, or motor function. It has approximately a 30,000-fold selectivity of NaV1.8 over NaV1.5, and NaV1.1/1.2.

Selective Sodium Channel Inhibitors: A Promising Therapeutic Class for Pain Control

Dr. Engle: Why are these drugs such promising therapeutic classes for pain control? Number one, they work in the peripheral nervous system and do not cross the blood-brain barrier, so we would not expect central nervous system effects from them.

They have no dependence for addiction or dependence for that same issue.

There is no concern for gastrointestinal or kidney toxicities like the NSAIDs, and there is no concern for respiratory depression or sedation like the opioids.

Approved and Investigational VGSC Modulators

There are also some other drugs that are currently being investigated. We have talked already about suzetrigine. It is an NaV1.8 inhibitor. Again, it allosterically binds the voltage-sensitive domain and blocks the channel in a closed state. It does not cross the blood-brain barrier. It is currently indicated for moderate to severe acute pain, including postoperative pain. It is FDA-approved as of January of 2025.

LTG-001 is another NaV1.8 inhibitor, and is peripherally acting as well. It is indicated for acute postoperative pain, and it is currently in phase IIb studies.

ANP-230 is a pan-peripheral NaV1.7, NaV1.8, and NaV1.9 blocker. It is being studied for rare genetic pain syndromes and broad-spectrum neuropathic pain. It has completed phase I trials and is currently in phase I/II trials.

With that, I am going to pass it over to Mandy.

Ouch Is Complicated: A Practical Approach to Acute Pain

Amanda Zimmerman (West Forsyth Pain Management): Thank you, Dr. Engle. Hi everybody. Mandy Zimmerman. We are going to talk about the practical approach to acute pain.

Understand the Type(s) of Pain When Considering Treatment Options

Just want you to remember that it is very, very important to identify the type of pain your patient is experiencing so you can really target your treatment to cover all those aspects of the type of pain. We are just going to go over those definitions.

Nociceptive pain is an inflammatory, kind of broken bone. It is a response to an injury or a stimuli. Typically, an acute situation. This includes postoperative pain, sports injuries, arthritis, sickle cell disease, mechanical low back pain. People would describe that as a dull ache. Sometimes it might be sharp, piercing pain, but it is just your response to an injury.

Neuropathic is an injury to the nervous system. This is typically chronic in response to possibly a nociceptive injury. Examples include post-herpetic neuralgia, trigeminal neuralgia, distal polyneuropathy, CRPS, radiculopathy. We have all seen those syndromes. Our patients describe those usually as burning, numbness, pins-and-needles sensation, sharp electrical shooting sensations. You really want to tease out what your patient is experiencing based on their descriptors.

Then we have nociplastic pain, which is a relatively new term. This arises from an altered nociceptive function. This is typically chronic. This presents typically as all-over body pain, which can present as fibromyalgia, people with irritable bowel, non-specific low back pain. Typically, that is a more long-standing presentation. They have nociplastic pain.

Typically, things are mixed pain. This is why we really want to focus our treatment based on the different types of pains that the patient is experiencing.

If they are postoperative, you have to think about what the particular surgery was. Do they have a greater chance of nerve injury associated with that surgery? Was it an abdominal surgery where there is a lot of visceral pain that is a lot of times referred. You just want to be thinking about the type of pain that you are dealing with.

Where Non-Opioid Analgesics Act Along the Pain Pathway

As you are thinking about what kinds of treatments you want to use for different types of pain, it is really a good idea to understand the pathophysiology of how pain is transmitted in the body. Basically, nociception, that is where you touch the hot stove, or you have the injury, and then that signal travels in the ascending pathway, through the dorsal root ganglion to the spinal cord, so it is in the peripheral nerves. Like Dr. Engle mentioned, there are sodium channels on these peripheral nerves that are responsible for sending that signal up to the spinal cord, and then we get the somatosensory cortex. Then, in the descending pathway, you have inhibitory things that come into play that quell those excitatory things.

There are different medications that work on those different pathways. In the ascending, we want to inhibit the pain transmission.

Then you have the things that are facilitating or activating the descending pain modulation. You want to upregulate those to inhibit the pain signal.

You want to be really thoughtful in the way that you are doing your polypharmacy per se, and then different drugs. We have got acetaminophen, aspirin, acetaminophen, mild to moderate pain. I was at a conference this weekend and they talked a lot about acetaminophen. We are understanding much wider mechanisms of action of acetaminophen that have been interesting.

Amitriptyline; that is your tricyclic antidepressant. Good for neuropathic pain and fibromyalgia. Duloxetine, good for neuropathic, chronic musculoskeletal pain, fibromyalgia.

Gabapentin is really good for neuropathic pain. Pregabalin the same. Lidocaine patch. That is just a non-specific sodium channel inhibitor. Then we have capsaicin and, of course, suzetrigine. Just be thoughtful about where your drugs work and what they are doing in the different pathways of pain transmission.

When Opioids Are Appropriate for Acute Pain: What to Use and How to Start

When are opioids appropriate? Like we said, opioids are not good or bad, but they do have risks. For acute pain, commonly prescribed are codeine, morphine, hydromorphone, hydrocodone, acetaminophen, oxycodone, oxycodone with acetaminophen.

For chronic pain, we use more buprenorphine, methadone, hydrocodone, extended release, extended-release morphine, tapentadol and oxycodone for chronic pain situations. Really, if we are talking about an acute pain, you want to stay away from those other modalities that are more used for chronic.

You want to really be careful about your patient selection. You want to consider when an opioid is appropriate. Consult the PDMP. You want to give them some naloxone for home use just in case. You just want to give them an as-needed versus around-the-clock dosing, prescribing an appropriate quantity.

We have a lot of quantity limits about opioids in place now from the legislators and regulators. You want to look at some screening tools as well. You just want to be thinking about all those things.

Pearls for Successful Outcomes

How can we have a successful outcome? You want to set the expectations early. I do not know. I see a lot of patients who have chronic pain that had no idea that their surgery was going to be as extensive as it was, and it was not really explained to them what to expect postoperatively. I think the ERAS protocol has done a really good job in setting realistic expectations for what their trajectory will look like in recovery.

You want to individualize the plan. Like I said, this is a personal experience, and different people respond in different ways, and you have to meet them where they are, understand all these factors: their anxiety, substance use, history, cultural factors, patient preferences.

You want to use multimodal analgesia, like I talked about the different targets, to really get the pain under control by hitting the different mechanisms of pain transmission.

You want to prescribe opioids thoughtfully. When indicated, use the lowest effective dose for the shortest appropriate duration.

I am going to hand it over to Kathy. Now she is going to talk about other stuff.

Pain, Pathways, and Picking the Right Plan: Rethinking the Acute Pain Toolbox

Kathy Kates (Pelvic Health Support): Thank you, Mandy.

Two Patients. Two Constraints. One Question: What’s the Best Pain Plan?

Acute pain management is a decision, not just a number to chase down. In a nationwide look at over 36,000 opioid-naive adults, about 6% went on to a new persistent opioid use, still filling prescriptions past 90 days. That rate barely moved whether the surgery was minor or major. That is roughly 1 in 15. What predicted it was not the surgery type; it was chronic pain history, tobacco use, and mood disorders.

Here is the frame for both cases today. Every first opioid prescription is a decision with real downstream risk attached. That does not mean never use one; it means use it deliberately as part of a plan, not as the only plan. We are going to talk through two patient cases in detail and learn how to build effective multimodal treatment plans when usual options are constrained.

Our first will be a 70-year-old man with a fracture waiting on surgery who cannot take an NSAID because of his heart. The second is a 35-year-old woman day of vascular procedure who cannot take NSAIDs because she started dual antiplatelet therapy status post iliac vein stenting.

Fracture Pain When NSAIDs Are Off the Table

Our 70-year-old male, he is opioid naive with coronary artery disease, hyperlipidemia, hypertension, and anxiety, sustained a displaced tibial plateau fracture in a fall at home. His ORIF is scheduled in five days.

Current medications are 81 mg of aspirin, atorvastatin 40 mg, lisinopril 10 mg, sertraline 50 mg, acetaminophen 650 mg every six hours. He cannot have NSAIDs because of his coronary artery disease. Notice he is already on an SSRI. That means we are going to avoid tramadol, and we are going to think twice about duloxetine. Gabapentin could be considered.

This is a mixed pain phenotype. Nociceptive plus neuropathic edge. It needs mixed mechanism treatment. NSAIDs are off the table, which is exactly why the channel inhibitor and gabapentin matter more for him than for a lower-risk patient. He is opioid naive, but he is not risk-free. His anxiety history, remember, the mood disorders, is a modest factor. This five-day window before surgery is a real opportunity to optimize, not just a delay.

Case 1: Build the Non-Opioid Foundation First

While we may not have standard protocols, we can create a structured multimodal plan based on his goals. Functional pain control, not zero pain.

I am curious, Dr. Engle, which would you layer in, and what would the dosing be? Any additional pearls that you have for us about if you would choose suzetrigine or perhaps if you would choose gabapentin.

Dr. Engle: I think this is a really interesting case, and it is one that is very common. I think that acetaminophen is a good drug in this context.

Looking at suzetrigine versus gabapentin, I think suzetrigine is actually a very good choice in this context. I’d load with 100 mg and then give 50 mg every 12 hours.

I think gabapentin is a maybe drug for him, but the risk factor here is that you have somebody that already has age, and if they are trying to ambulate, they have increased risk of falls and already have a leg injury. That is certainly a significant risk factor in this context.

Then I think using a low-dose opioid is appropriate as a rescue in this context as well.

Kathy Kates: Excellent. Thank you. Anyone else on our panel? Mandy or Michael, anything to add as we look at his multimodal plan, rescue meds, and his assessment?

Dr. Sprintz: Yes. First of all, Mitch's plan makes sense, and it is a great starting point. The key thing with all of our patients is we need the ability to reassess and have a plan B. I think that is a really key point here where while this may manage all the pain and we are good to go, what do we do if the patient calls up and they say, "Doctor, I am hurting incredibly still"? It is not covering that. We know that we have got five days to surgery. This would be a situation where it may be appropriate for a very short course of opioids as a rescue in that situation. Hopefully not, meaning that we have it and this patient is opioid naive, but they have a tibial plateau fracture, and we also know it is short and limited. It is important always to remember that we look at the whole picture, instead of just saying, "Nope, you just got to suck it up until surgery." That is not the best option at that point. I would be more apt to either add gabapentin or a short course of the opioid for a short period of time in order to help manage him for that period until we can get to surgery.

Kathy Kates: Thank you.

Amanda Zimmerman: I agree. Just to mention, looking at his home situation, I think we need to really focus on what support is during these five days before surgery. How much support does he have? I think that would really guide our treatment options as well. Talking to his wife, talking to his daughter, whoever is there with him about the different medications that we are using and watching out for any risk, fall risk, if we are going to choose gabapentin. I want to mention too that we see a lot that gabapentin is misused for nociceptive pain. This is more of a nociceptive pain situation. You really would not want to use it unless he had a neuropathic pain component, which we described earlier. I just want to mention those.

Kathy Kates: Excellent points. Thank you.

Acute Pain After Iliac Vein Stenting

We will move on to Case 2, which is a 35-year-old woman, multiparous G3P3 with endometriosis and pelvic venous disease. She is opioid naive with venous origin, chronic pelvic pain for the past 14 months, confirmed on venography to be found from a left common iliac vein compression lesion, which is May-Thurner syndrome, which has been refractory to conservative management.

She underwent left common iliac vein venoplasty and stenting today, performed because conservative therapy failed, not as an elective or discretionary procedure. Now she has acute post-procedural pain. It is primarily nociceptive, but she does report some occasional stabbing burning at the femoral venous access site and intermittent burning at the left flank.

She has long-standing pelvic pain and says specifically that this pain is different. Her current medications: she is on a drospirenone-containing OCP for ovarian suppression. Now she is on aspirin 81 mg and clopidogrel 75 mg for her dual antiplatelet coverage for her stenting protocol and 650 mg of acetaminophen every six hours.

Minimal relief, no home opioids. Remember, NSAIDs are out for her. She works a standing job, nursing - prolonged standing is a known aggravating factor for her underlying condition - and she is the primary caregiver for three children. We are motivated to avoid sedation, and we want to get her back to return function as quickly as we can.

Match the Mechanism, Then Name the Tradeoffs

For her non-opioid options, we want to build the same foundation that we built for our previous 70-year-old male. Here is where duloxetine - might be worth naming - not for him, but maybe for her. Again, we use it off-label as a multimodal adjunct for acute postoperative pain, typically 60 mg starting one to two hours before the procedure and continued up to 14 days. The evidence is mixed, so it is a reasonable adjunct to raise, but not a proven standalone option.

One thing worth flagging for her specifically: duloxetine, like SSRIs, can modestly increase bleeding risk. We want to consider that because she is on dual antiplatelet therapy.

Then her contraception: she is on drospirenone, a fourth-generation progestin. If you decide to start suzetrigine, it is a CYP3A4 inducer. It makes certain types of birth control less effective, so you need to make sure you are checking it. She has two options: she can switch to a different generation progestin, a second-generation progestin, levonorgestrel or norethindrone, which suzetrigine does not have a meaningful effect, or she can stay on and add a nonhormonal backup method like condoms for the duration and for 28 days after discontinuation.

This is the kind of interaction that often gets missed. Now you will not miss it because we have heard it here.

Panel, I would love to open it up to you - Mandy, we will start with you - about what other options you might consider or additional thoughts that you have to get our 35-year-old mom of three out of pain.

Amanda Zimmerman: Yes. We are not going to get her out of pain, but -

Kathy Kates: We will get her back to normal functioning.

Amanda Zimmerman: I think the scheduled acetaminophen is very good. We cannot do the NSAID. Of course, suzetrigine would have a place here, I believe. I would give her a loading dose and then twice a day just to get things under control. Duloxetine, I think, is a really good option. Again, understanding her, I mean, pelvic pain is tough. Endometriosis visceral pain is very referred, very wide-ranging, so it can be very debilitating. I think understanding and meeting her where she is a key piece of this. Reducing catastrophizing is key as well. I think duloxetine has a place, suzetrigine would be good. Dr. Engle, do you have any other input?

Dr. Engle: I was going to put in here that I think that duloxetine is a fantastic choice. I think it is one of the under-recognized drugs you can certainly use with some of the visceral pain symptoms here. I think that is a great choice. I also think suzetrigine is a great choice, just understanding the context and what it means in terms of how that will possibly change her management should she elect to proceed with it.

Kathy Kates: I think that, pulling both cases together, suzetrigine is one real tool. We now know the mechanism, the dosing, we know who it is for, and we know its limits. There is no standard protocol, but there is multimodal mechanism-based approaches that we apply consistently whether the pain is in a fractured tibia or after a pelvic procedure.