In the next section, we'll discuss some pharmacological agents that we can use for patients that have some pain. These will include non-opioid and opioid medications. There are many types of non-opioid pain medications that you can reach out to when a patient has different types of pain. A lot of times, patients do not want to get opioid medications because they know of the adverse effects that they can cause. So knowing different types of these will help you utilize pain medications to your advantage. Some of those can be non-steroidal anti-inflammatory drugs, acetaminophen, neuropathic agents, antidepressants, and muscle relaxants. We'll get into more of these in the next few slides. As you can see here, there are many different types of groups of non-steroidal anti-inflammatory drugs. In each group, you'll probably see some common over-the-counter anti-inflammatories, such as ibuprofen, naproxen, aspirin. In the acetic acid derivatives, you'll see a little bit less common, but indomethacin, etotolac, catorolac, and diclofenac. Meloxicam is in its own class. And then there's also salicoxib, which is a selective COX-2 inhibitor. These work on the body by inhibiting the activity of cyclooxygenase enzymes, also known as COX-1 enzymes and COX-2 enzymes. COX-1 impacts the gastrointestinal mucosa, the renal function, and coagulation, while COX-2 works on the inflammatory and pain aspect, but also there's an increased risk of cardiovascular events with more COX-2 selective insets. So there's a balance. If someone has more hypertensive and cardiac issues, you might not want to pick a COX-2 for that patient. Or if you know a patient has GERD or coagulable or renal impairment, you might pick a COX-2 inset. On the bottom there, we talk about using caution in patients with renal impairment, acid reflux, or stomach lining dysfunction, such as ulcers, patients with hypertension or heart disease, and bleeding disorders. Another very common over-the-counter medication that we tend to go towards is acetaminophen. This will help with patient's pain and is also an antipyretic. So if they have a fever, it will help bring that down. It inhibits central prostaglandin synthesis. It does not have effect on platelets or gastric mucosa. So if patients have bleeding disorders, they're on anticoagulation, or they have stomach issues, this is a safe medication for them. One thing you do have to worry about is that it can cause hepatotoxicity if used in excess, or if they have underlying liver issues, you want to be cautious with them. Another drug class that we tend to go towards if a patient is having neuropathic pain is neuropathic agents. These can come in two different broad categories. One is sodium channel blockers, and the other is calcium channel antagonists. In the sodium channel blockers, you have the tricyclic antidepressants, antiarrhythmics, local anesthetics, and antiepileptic or anticonvulsants. In the calcium channel antagonists, you have things such as gabapentin and pregabalin. Here are some examples of some sodium channel blockers, such as phenytoin, carbamazepine, oxycarbazepine, valproic acid, lamotrigine, topiramate, and levotirisamine. These all work by blocking the sodium channels, which prevents the release of excitatory glutamate and inhibits ectopic discharges. Some common uses of sodium channel blockers can include trigeminal neuralgia, chronic regional pain syndrome, diabetic neuropathy, radicular extremity pain, chemotherapy-induced peripheral neuropathy, and also post-traumatic neuralgia. A local anesthetic that we use for neuropathic pain is lidocaine. It can block the aberrant firing of abnormal nerves. We use this in post-traumatic neuralgia, trigeminal neuralgia, radiculopathies, and also peripheral neuropathies. Probably the most common neuropathic pain medication that we will use is the calcium channel blockers gabapentin and pregabalin. They work by binding to a voltage-gated calcium channel, which decreases the release of glutamate, norepinephrine, and substance P. We use these in post-traumatic neuralgia, chronic regional pain syndrome, painful diabetic neuropathy, radiculopathies, HIV-associated neuropathy, GBS, and also phantom limb pain. Another non-opioid pain medication class that we use is the antidepressants, tricyclic antidepressants. Commonly, these are used as amitriptyline or nortriptyline. They work by inhibiting the norepinephrine and serotonin reuptake in inhibitory descending pathways. They are metabolized by the liver and cleared through cytochrome P450, so you do not want to prescribe in conjunction with other SSRIs, which can increase the TCA plasma levels. It can also prolong the QTC interval. Patient tolerance is dictated by antihistaminic and anticholinergic side effects. Another class of antidepressants are the SSRIs or the selective serotonin inhibitors. Examples of these include citalopram, fluoxetine, paroxetine, and sertraline. They work by inhibiting presynaptic serotonin reuptake in the central nervous system. They are commonly used for depression, but they also might help a little bit with pain management. They are also metabolized by the liver, so you want to be cautious with patients with liver impairment. The last class of antidepressants that we'll touch on are SNRIs or serotonin norepinephrine reuptake inhibitors. Examples of these are venlafaxine and duloxetine. Just a note that venlafaxine can cause hypertension, so you want to be careful when prescribing that. They work by inhibiting the serotonin and norepinephrine reuptake. This was approved in the United States for diabetic peripheral neuropathic pain, fibromyalgia, general anxiety, and depression. It's the only approved medication for psychiatric and painful conditions. Caution, though. When given in combination with other SSRIs, TCAs, MAOIs, tryptans, tramadol, this can cause serotonin syndrome. And lastly on our non-opioid pain medications are muscle relaxants. Examples of these can be cyclobenzaprine, methocarbinol, tizanidine, and baclofen. For tizanidine, the mechanism of action is centrally acting, being an alpha-2 adrenergic agonist, and baclofen mechanism of action is a GABA-B antagonist. They're kind of unsure what the mechanism of action is for the cyclobenzaprine and the methcarbinol. Use of these can include cervical and lumbar spinal pain, and they can be used to treat cervical and lumbar spinal pain, muscle spasms and strains, myofascial pain, and low back pain. These are not all the non-opioid pain medications that we use, but these are very common ones that you will commonly prescribe in a pain management practice. Opioids are the next category of medications that will be covered in this topic. They can be utilized for pain management. However, they are very controversial for non-malignant chronic pain. They are known to produce reliable analgesia and can be an integral part of a multidisciplinary approach to patient care in the appropriate setting. Opioids have a mechanism of action in the central nervous system and in the peripheral nervous system. They are known to bind different receptors, including mu, kappa, and delta receptors. At the presynaptic level, in sensory C-fibers, opioids are thought to reduce the influx of calcium to reduce neurotransmitter release. At the postsynaptic level, they are thought to increase potassium influx into the cell in order to hyperpolarize second-order neurons. There are various opioid receptor types, as mentioned earlier, including mu1, mu2, delta, and kappa. And as this slide shows, there are various effects from opioids interacting with these receptors. It is important to note that the mu1, delta, and kappa receptors all have analgesic properties. This slide covers opioids that are used for mild to moderate pain. And some of these medications are combined with non-opioid analgesics, such as aspirin, ibuprofen, or acetaminophen. It is important as a clinician to be mindful of the non-opioid analgesics that the patients are taking in combination with opioids and outside of this regimen in order to avoid toxicity. Hydrocodone, oxycodone, and codeine are several examples of mild to moderate pain-relieving opioids. Other medications include tramadol, which has some weak norepinephrine and serotonin reuptake inhibition properties. Another similar medication is tepentadol, which has mu opioid agonism properties, as well as norepinephrine reuptake inhibition properties. Tepentadol is also considered by some to be useful for neuropathic pain. Another important point to note is that patients who have cytochrome P450 2D6 poor or ultra rapid metabolism can have inadequate analgesia or toxicity related to these opioids. Morphine is another common opioid that is often used for moderate to severe pain, and it acts at the mu receptor as an opioid agonist. It is available in various formulations, including oral, intravenous, epidural, and intrathecal. And it is also available in instant release and long-acting release formulations to be taken by mouth. Morphine is the benchmark to which other opioids are compared in terms of dosing and analgesic potency. As you can see on the slide, MME, which stands for Morphine Milligram Equivalence, is equal to 1 for morphine, and other opioids are compared to morphine in such a manner. So, as you can see, the next medication on this list, oxycodone, has a morphine milligram equivalent of 1.5. Now, it is important to note that there are various references available for MME calculation and conversions, and it is important to be really familiar and have appropriate training in order to convert patients from one opioid to another. This slide highlights several additional opioids that are used for moderate to severe pain, and these particular opioids are considered more potent. Oxymorphone is a faster-acting opioid compared to morphine, and hydromorphone has similar duration of analgesic effect, and it is considered to be more potent than morphine. Fentanyl is also a mu-opioid receptor agonist, however, one should use caution when calculating MME conversion from other opioids to fentanyl because of various formulations, and the fact that fentanyl is prescribed in microgram dosing. The next slide shows the effects of fentanyl on pain. Fentanyl is a mu-opioid receptor agonist, however, one should use caution when calculating is prescribed in microgram dosing. This slide covers two opioids that are utilized for dependency in certain situations. Methadone, being one of them, is a mu and delta agonist, as well as a norepinephrine and serotonin reuptake inhibitor. Methadone is also known to have some NMDA antagonist activity. It is important to note that methadone does have unpredictable bioavailability, and there is high inter-individual variability in terms of dosing. Another important point with methadone is that it can prolong the QT in terms of potentially causing a serious arrhythmia, therefore, it should be used with caution. The other medication is buprenorphine. And it has unique properties in that it is a partial mu-opioid receptor agonist and antagonist at the kappa and delta receptors. You may see buprenorphine combined with mu-opioid receptor antagonist, such as naloxone, in certain formulations. Over the past several decades, the United States has seen a significant increase in drug abuse-related overdoses. As seen in this graph from 1970 to 2007, the rate of unintentional drug overdose deaths has increased dramatically. And it is believed that this is driven by increased use of opioid analgesics. CDC has provided guidelines in 2018 for prescribing opioids for chronic pain, and these guidelines will likely change over time, but they are listed here for your reference. It is important to note that per CDC, opioids are not first-line or routine therapy for chronic pain, and clinicians should establish and measure goals for pain and function with their patients, including a discussion of benefits and risks and availability of alternative non-opioid therapies. In general, it is important if you are going to prescribe opioids for chronic pain that you start low and go slow, including starting with immediate-release opioids instead of long-acting opioids. In the setting of acute pain, a clinician should not prescribe more than what is needed for the patient for the acute period of pain. Extended-release and long-acting opioids are not ideal for acute pain management. For patients who are being prescribed opioids for chronic pain, there should be routine follow-up and reevaluation of patients to evaluate benefits and risks. There should be consideration of a reduction in dose or tapering and discontinuation of the medication if needed. In states where it is available, a prescription drug monitoring program should be utilized to check patients' prescriptions, the locations where they are being filled, and to see if there are multiple providers providing opioids for the same patient. Clinicians should consider using urine drug testing to identify prescribed substances and any undisclosed illicit drug use. For patients who are being managed with opioid therapy for chronic pain, it is imperative to have appropriate documentation and evaluation. This evaluation and documentation should include the five A's that are listed in the slide, including evaluation and documentation of activity slash activities of daily living as it relates to the effects of the opioid therapy on their ability to function. One should also document analgesia in terms of how effective the opioid therapy is in reducing the patient's pain. One should also evaluate and document if the patients are having any adverse effects and if there's any signs of aberrant behavior or mood impairment going on while you're treating the patient. Many patients who have chronic pain also have concurrent psychological conditions and substance abuse issues. It is important as a clinician that each patient be screened by the clinician for past history of substance abuse and mood impairment. Some of these patients may require co-management with psychiatrists or addiction specialists. If a patient has a drug use disorder and is being prescribed methadone or other medications in that category for a drug use disorder, they should be done under appropriate setting and in the care of a physician who is licensed to prescribe these types of medications. It is important to have an opioid contractor agreement where the clinician and the patient where the clinician and the patient have agreed upon the rules involved in the care of their chronic pain. For many patients, random or periodic drug toxicology screening of urine and or saliva is an important part of their treatment compliance.

pharmacological agents

pain management

non-opioid medications

opioid medications

NSAIDs