Hopefully, the next couple of talks will give people something for their tool kit. So Dr. Ben-Chayim from UCSD is going to be speaking about non-opioid pharmacotherapy for pain. Okay, good afternoon, everybody, and thank you for being here. Thanks for braving the very last session of the AANS this year. And I'll be talking a little bit today, reminding us about the different options we have for non-opioid pharmacotherapy, and how do I advance? Okay, so why are we even having this talk about non-opioid pharmacotherapy? Well, many thanks to Dr. Follett, our excellent Loeser lecturer, for bringing this all into perspective for us. And I have a slide that may answer a question that was in the audience earlier that really just elucidates the problem. We have an opioid crisis or an opioid epidemic right now in the United States, and we all know that there's been a marked use in prescription opioids really from the 1990s and steadily increasing until now, when attention has been called to this issue. And we also found that opiates are not harmless, aside from the side effects that we all know about, including nausea, vomiting, constipation, ileus, bladder dysfunction, etc., etc. There is a significant component of long-term physical dependence and the liability for addiction. And then, of course, last but not least, there is a side effect of ventilatory depression, which can lead to death. And so, over the years, this crisis has seen a substantial rise in opioid-related deaths and some staggering statistics, including the number of deaths that we see here from synthetic opioids in 2016 and how it's rising, and the fact that millions of people are meeting criteria for substance abuse disorders secondary to prescription opioids. And also, the people, like Dr. Follett mentioned, who report, you know, for example, going into their heroin addiction because of initially being exposed to prescription opioids. So furthermore, we really ask ourselves the question, are opiates actually effective at accomplishing our goals, which are pain reduction and ultimately improved quality of life? And so, while we know that there is a role for opiates in the acute settings, more and more studies are coming out that are showing us that this is really not necessarily the case, particularly in the chronic pain setting. So this is a study that was published just several months ago in JAMA that basically asked the question, does opioid use lead to better pain-related function or decreased pain intensity at 12 months? And what they did is they took a group of 256 patients, or sorry, 265 patients from the VA, that had either moderate to severe back pain or knee pain or hip pain from osteoarthritis, which are the most common reasons people start opiates, and they randomized them to an escalating regimen of either opiate versus non-opiate therapy. And they used pain-related function as a primary outcome measure and pain intensity as a secondary outcome measure. And so what did they find? Well, their primary outcome measure, pain-related function at 12 months, they found no significant difference, actually, between the opioid group and the non-opioid group as measured by this brief pain inventory interference scale, which is really a rating scale of the quantity that pain interferes with daily activities like sleeping, working, mood, et cetera, with a P value of 0.58. Also interestingly, they found that there is a small but significant difference in pain intensity at 12 months, which with, in fact, the non-opioid group reporting better pain relief than the opioid group at 12 months with a P value of 0.03. They also looked at adverse outcomes, and perhaps not surprisingly, they found that the opioid group reported significantly more medication-related symptoms than the non-opioid group. Essentially, multiple studies are showing us that opioids are not, in fact, a panacea for pain. Again, while they do have a role in the acute settings, their role, especially in chronic pain, is coming into question. Are these really effective? And so studies are consistently reporting a lack of improvement in outcome measures like health-related quality of life, even outcome measures like pain intensity, as I showed, and this is despite escalating doses. You know, some, both human and animal studies also report opioid-induced hyperalgesia. So perhaps we're actually going against the goals that we're trying to accomplish. And this is a cross-sectional study. It was an observational study that looked at 10,000 patients from Denmark that looked at a control group and a pain group in measures of the SF-36 quality of life subscale and showed that the opioid group consistently scored lower, which was poorer outcomes. The opioid group as opposed to the control group, and then more interestingly, as opposed to the group that was not taking opioids. So we're seeing over and over again that patients that are on opiates are not achieving these outcome measures. So what can we do? What is this whole group of drugs in the non-opiate pharmacotherapy repertoire? So just very briefly, they include things like local anesthetics, NSAIDs, acetaminophen, other medications which we'll briefly talk about, and then there are, I'll very briefly talk about non-pharmacological options. So starting with local anesthetics, they're incredibly potent drugs, particularly also to be considered in the perioperative period when we want to reduce the amount of opiates. We might still need them, but it would be helpful for patients to not take as many. They can be used with other adjunctive drugs. They've come in a variety of forms, subcutaneous, subfascial, topical patches, as injections into the spinal cord, into the epidural space, and the perineural regions, also into facets. And I'll call your attention to one that perhaps is underutilized, liposomal bupivacaine, which is actually approved to be injected at the end of a surgery into the surrounding tissues. It's under the trade name of Expirel. And it's designed to have a slow release over 72 hours of bupivacaine to really improve pain relief in this immediate perioperative period where it tends to be the most salient. So also, we have NSAIDs and COX-2 inhibitors subset, as well as acetaminophen, which are really powerful drugs, which can decrease pain without all of these opioid-related side effects in the perioperative period, as well as in the chronic pain setting, and have been shown over and over again to lead to improved recovery, specifically when we use them as part of a multimodal strategy. IV acetaminophen was approved in the United States in 2010 and is a very potent medication with peak plasma concentrations within 15 minutes. Goes by the trade name of Ofirmev and is one that we should be particularly aware of. And then there is really a whole host of other drugs that can be used both in the perioperative and in the chronic pain setting. Alpha-2 adrenergic agonists like clonidine and dexamethasone, specifically in the perioperative period. NMDA receptor antagonists like ketamine and dextromethorpan, ketamine being thought to actually sensitize you centrally to opiate receptors. Gabapentanoids, we all know, are particularly useful in the setting of neuropathic pain syndromes. And then glucocorticoids, which are very potent anti-inflammatories, dexamethasone probably being the most commonly used in neurosurgical practice. So when given all of these options, how do you establish a treatment plan for your patients? I think it's first important to really just think about disease burden and establishing goals of care. And this can be very different in the chronic pain setting versus the palliative care setting. And so we really want to think specifically and saliently about non-opioid pharmacotherapy when it's really important for us to establish these restorative goals, like returning to work, self-care, increased activity, functional restoration, where perhaps in the palliative care settings, those are not our primary goals. Our goals are rather comfort, support, and easing pain and suffering. And this, of course, plays a big role in what medication regimen we're going to use. So the second most important thing to think about is to try to tailor medication regimens by thinking about the primary physiologic type of pain and the primary source of pain. Is it nociceptive or neuropathic? If it's nociceptive, is it mainly inflammatory? Is it mechanical? Is it bone pain? Is it coming from muscular sources? And then, of course, there's always the psychogenic components of pain, which can be its own pain generator or can be an adjunct to an existing component of pain. So with nociceptive pain, we have many potent management options, including the NSAIDs, which I mentioned, ibuprofen, naproxen. Ketorolac or Toradol can be very potent in its IV formulation in the postoperative period. As neurosurgeons, we're often very worried about using this medication because of its potential antiplatelet effects, although there really have been now several randomized trials, including some pretty impressive meta-analyses that have shown that really, actually, this does not bear out as an increased risk of bleeding in the postoperative period. Even despite that, with all of that data, we still worry about it. And then there's the selective COX-2 inhibitors, and then, of course, corticosteroids. For muscular pain, we want to think about the judicious use of muscle relaxants, actually trying to target the source of pain in these spasmolytics, which can have effects both centrally and at the neuromuscular junction, things like Flexeril and various other muscle relaxants, including Valium. Neuropathic pain is particularly difficult to treat, as we know, but it's also typically not responsive to opiates, even though we've all seen these patients come through our practice on 100 morphine equivalents or more for something that just does not treat the primary etiology of neuropathic pain. So in neuropathic pain, we really want to think about things that actually aim to treat the etiology, like anticonvulsants, gabapentin, carbamazepine, of course, especially important in trigeminal neuralgia, lamotrigine, topamax, just to name a few. Also antidepressants have been shown to be quite effective, local anesthetics, as we mentioned earlier, and capsaicin, which is something we don't often think about but can be available in topical formulations or as pills. And then, lastly, psychogenic pain, which is also quite difficult to treat. It's a complex issue. Really, sometimes it's a strong additional component to an already existing physiologic chronic pain syndrome. But nonetheless, this is pain that has to be treated. Ideally, this is treated in a concerted way, along with our psychiatric colleagues who can also prescribe psychotherapy, but may include medications like antidepressants, various anxiolytics, and atypical antipsychotics. Percutaneous interventions, I'm sure we all use in our practice or send to our interventional colleagues, peripheral nerve blocks, sympathetic blocks, epidural blocks, other types of localized blocks that aim to actually go to the source of the pain generator. And then, of course, we can't forget the case of intracerebral pumps, which, of course, are FDA-approved for the use in morphine, but also for the non-opioid medications, like Baclofen in the case of spasticity, Clonidine, Bupivacaine, and then Ziconotide, which is a very interesting medication that I'll just briefly touch on because it gives us hope that new things are constantly being discovered. Ziconotide is a medication that was isolated from this Conus magus sea snail that's indigenous to the Red Sea and also in the Philippines. It is a voltagated calcium channel blocker and pharmacologically distinct from other pain medications that we had previously. And we don't really exactly know, but it appears that this inhibits the release of these pronosusceptive chemicals at the level of the spinal cord and actually also in the central nervous system in the brain. And it's approved right now for the treatment of severe chronic pain, most commonly used with neuropathic pain. And it is somewhat sad because it seems like there are things that are preventing the use of this, even though it doesn't lead to the development of addiction or tolerance. It seems like logistical challenges are slowing the utilization of this, including titration issues, the fact that it's only labeled for monotherapy. And it can be quite difficult to obtain, but nonetheless, something we should all keep in mind. Let's not forget also about topical analgesics that can be very effective. There are so many formulations of this, and they can be compounded together, including lidocaine patches and gels, topical diclofenac, ketoprofen, gabapentin, morphine, topical capsaicin. These are very good for localized pain syndromes and can also be used for things like, for example, atypical facial pain syndromes can be extremely effective. And of course, we'll always mention cannabis. The jury is still out on actual evidence of how effective this is, but as of 2016, it's been legalized for medical use in 25 states. It's increasingly being legalized also for recreational use. And what we're seeing is both a formal and an informal transition of patients going from opiates to cannabis. And there's a suggestion that this actually is decreasing rates of opioid addictions and opioid-related deaths due to overdose. And we know it's at least moderately effective for chronic neuropathic pain and, of course, cancer-related pain. It can have a lot of other actual beneficial side effects, like in cancer-related pain, like being an appetite stimulant and so forth. And of course, we also have non-pharmacological treatments for pain, which I won't go into in depth, but things that we should also, of course, remember, things like transcutaneous electrical nerve stimulation, physical therapy, which can relieve pain, massage therapy, and then relaxation techniques, including meditation, which can be very effective to help as adjuvant therapies. So in conclusion, we know that opioids have significant side effects. They can cause dependency and, of course, they can be lethal. And also, they're not necessarily effective at accomplishing our goals, particularly in the setting of chronic pain. And we have to remember that there are a diverse range of pharmacological and non-pharmacological non-opioid options to choose from that are quite effective. So, thank you very much. Thank you.

non-opioid pharmacotherapy

pain management

opioid crisis

pharmacological treatments

non-pharmacological treatments