Pain Management: Module II

Pain **Pain** is something most of us are familiar with and experience at some point in our lives. All pain is uncomfortable, unwanted, and unpleasant, whether it be emotional or sensory pain. Pain isn't something we can objectively and definitively measure. It is different for everyone, and so it...

Pain **Pain** is something most of us are familiar with and experience at some point in our lives. All pain is uncomfortable, unwanted, and unpleasant, whether it be emotional or sensory pain. Pain isn't something we can objectively and definitively measure. It is different for everyone, and so it's the **perception of pain** that we are treating. That is why we cannot treat the "same" pain the same way. Let\'s watch an overview of the pharmacodynamic process before diving into the details in the proceeding lessons. **Pain** The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." Pain can range from mild to severe and has the ability to negatively affect quality of life. There are two general types of pain: **acute **and **chronic**. **Acute Pain** **Chronic Pain** ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Acute pain is a result of acute illness, surgery, trauma, labor, or a specific disease. It serves a useful **biologic purpose**, is associated with **skeletal muscle spasm** and **sympathetic nervous system activation**, and is typically **nociceptive**. Chronic pain, in contrast, may be considered a **disease state**. It is pain that **outlasts the normal time of healing** if associated with a disease or injury. Chronic pain may arise from psychological states, serves no biologic purpose, and has no recognizable end point. Chronic pain is responsible for **changes in nerve function and transmission over time**, and can be either **nociceptive** or **neuropathic**. There are multiple strategies to manage both chronic and acute pain. The goal of pain management strategies, however, remains the same. The goal is to:  - - - - The chart below shows each pain management technique. **Non-Pharmacologic Strategies** **Pharmacologic Strategies** ----------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------ These include relaxation techniques, acupuncture, nerve stimulators, heat/cold applications, and massage. These include non-opioid medications, opioids, and adjuvant therapies. **Categories of Pain** Pain is most often classified by the kind of damage that causes it. The two main categories are pain caused by **tissue damage**, also called **nociceptive pain** (somatic and visceral), and pain caused by **nerve damage**, also called **neuropathic pain** (positive and negative). A third category is psychogenic pain, which is pain that is affected by psychological factors. We will be focusing on the first two categories of pain in this module. **Nociceptive Pain** People feel this kind of sensory pain when specific nerves, called **nociceptors**, detect **tissue damage** and transmit information about the damage along the spinal cord to the brain. There are two types of nociceptive pain --- **visceral **and **somatic**. A diagram of different types of muscles Description automatically generated Nociceptive **somatic pain** can result from injury to skin, muscle, soft tissue, or bone. It is usually localized, can be constant or intermittent, and is often described as gnawing or aching pain that may become sharp with movement. Potential causes of somatic pain include: - - - - Nociceptive **visceral pain** is pain that arises from internal organs. It is typically less localized, is usually constant, and may be referred (for example, diaphragmatic pain may manifest itself as shoulder pain). It is often described by a variety of terms such as aching, squeezing, and cramping. Potential causes of visceral pain include: - - - - - The basic **mechanism** for nociceptive pain undergoes three events --- **transduction, transmission, and modulation** --- in the presence of noxious or unpleasant stimuli (pain). - Transduction occurs along the nociceptive pathway in this order: - - - - Transmission generally occurs in two stages: - - - Modulation takes place at all levels of nociceptive pathways through the primary afferent neuron, DH, and higher brain center by up- or down-regulation. The following all play an important role in modulation:  - - - **Neuropathic Pain** **Neuropathic pain** is caused by **damage or impairment to the nervous system**, and is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). Neuropathic pain may be generated by either the peripheral nervous system, such as an alteration in fiber sensitivity or the development of collateral nerve fibers, or the central nervous system, such as in cases of hyperexcitability of central neurons, NMDA activation, central disinhibition, or both. Examples of neuropathic pain include: - - - - **Evaluating Pain** Since pain is subjective, **self-report** is considered the gold standard and most accurate measure of pain. The **PQRST method** of assessing pain is a valuable tool to accurately describe, assess, and document a patient's pain. The method also helps when selecting appropriate pain medication and evaluating the response to treatment. **PQRST Method** Select the arrows below to learn more about the PQRST method.  - - - - - - - - - - - - - - - - - - - - - - - - - - - - **The WHO Pain Ladder** The World Health Organization (WHO) created a practical pain ladder diagram in 1986 to help guide clinicians around the world in the administration of pain medication for cancer patients. The pain ladder was designed intentionally to be extremely simple: there are three steps to the ladder, each corresponding to increasing pain intensity. The clinician prescribes medications as pain worsens, moving from one rung to the next. Pain therapy is therefore based on pain intensity and patients progress through the steps one by one --- from lowest to highest --- until pain is relieved. The terms "weak" and "strong" opioid are hardly used today but are readily understandable, even if it is more useful, perhaps, to speak in terms of dose. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- **Step 1** **Step 2** **Step 3** ----------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Non-opioid analgesics are prescribed at this step, such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs). If the pain persists or worsens, the clinician prescribes pain relievers described as "weak opioids," with or without a non-opioid or adjuvant therapy. The WHO pain ladder lists codeine, hydrocodone, and tramadol as "weak opioids." At this point, if pain persists or worsens, the patient is administered a "strong opioid," with or without a non-opioid or adjuvant therapy. The WHO Pain Ladder lists morphine, oxycodone, methadone,\  hydromorphone, and fentanyl as "strong opioids." ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------  Non-opioid Analgesics - Part 1 **Analgesics **are medications that **relieve pain**. There are three main types: non-opioid analgesics, opioid analgesics, and compound analgesics that combine the two previous forms. **Non-opioid analgesics** are commonly used to treat mild to moderate acute and chronic pain. Most non-opioid analgesics work by reducing inflammation at the site of pain. They can be used as monotherapy, but they have greater efficacy in combination with opioids. As opioid prescriptions decline, non-opioid analgesics are **increasingly emphasized** in a variety of clinical settings as a preferred, safe, and effective first-line therapy. Unlike opioids, long-term use of non-opioid analgesics does not lead to physical dependence. **Acetaminophen** Acetaminophen, commonly abbreviated as APAP, is a class unto itself and works to reduce both pain and fever. It works by changing the way the body senses pain and by cooling the body. Acetaminophen is a centrally-acting weak COX-1 and COX-2 inhibitor, and may activate serotonergic pathways. Select the headings below to learn more about considerations for the administration of acetaminophen. **Therapeutic Use\ ** Acetaminophen is used to relieve mild to moderate pain from headaches, muscle aches, menstrual periods, colds and sore throats, toothaches, backaches, reactions to vaccinations, and to reduce fever in children. It can also be used as an adjunct in the treatment of severe pain. Acetaminophen is a **first-line analgesic** to relieve the pain of osteoarthritis (arthritis caused by the breakdown of the lining of the joints), although it **does not provide anti-inflammatory benefits.** It is widely considered to be the safest analgesic available, although **liver injury** is a concern with overdose. **Dosage and Administration\ ** Acetaminophen comes as a tablet, chewable tablet, capsule, suspension or solution (liquid), extended-release (long-acting) tablet, and orally disintegrating tablet (tablet that dissolves quickly in the mouth), to take by mouth with or without food. It also has an intravenous formulation used primarily around the time of surgery and is used as multimodal pain management. The dosage recommendations for acetaminophen are as follows: - - - It is important to note that some formulations contain benzyl alcohol, propylene glycol, or polysorbate 80, which you may want to avoid in certain patient populations, such as those with alcohol use disorders. There are many **combination products**, which is important for patients to be aware of so that they do not go over the recommended **total daily dose of 4 grams per day.** **Adverse Effects\ ** Acetaminophen is usually well tolerated in therapeutic doses, but it can cause adverse effects, most of which are associated with acute or chronic overdose. Hypersensitivity reactions include: - - - - - - - **Warnings and Contraindications\ ** **Contraindications** - - - **Warnings/precautions** - - - **Pregnancy and Lactation\ ** Acetaminophen is a first-line analgesic in pregnancy if non-pharmacologic therapy is inadequate as it is not generally considered teratogenic. It is excreted in low concentrations in breast milk. **Overdose** Acetaminophen **toxicity or overdose** can occur purposefully (when a person knowingly takes more than the recommended maximum daily dose) or accidentally (when a person is unaware they are taking multiple products containing acetaminophen and exceed the recommended maximum daily dose). Acetaminophen toxicity is the leading cause of **drug-induced liver failure, suicide-related death, and unintentional overdose**. An overdose occurs when too much acetaminophen overwhelms its pathways for metabolism and elimination. When a patient ingests too much acetaminophen, there is a larger amount shunted through metabolism by CYP 2E1. This leads to increases in a toxic metabolite or NAPQI, which requires conjugation with glutathione for elimination. Stores of glutathione can become easily depleted leading to increased levels of the toxic metabolite NAPQI, causing liver toxicity. The primary way to** treat acetaminophen overdose** is to replete glutathione stores by **administering N-acetylcysteine**. A diagram of a flowchart Description automatically generated **Management of Acetaminophen Overdose** The management of the acetaminophen-poisoned patient may include **stabilization, decontamination, and administration of N-acetylcysteine**, a specific antidote. The duration of N-acetylcysteine treatment is determined by the type of ingestion and the presence or absence of elevated liver function tests (LFTs). The initial management of acetaminophen poisoning is determined by the patient\'s presenting symptoms. Most patients who present early (within 24 hours) after an acute acetaminophen ingestion are asymptomatic, while others may require treatment for symptoms related to coingestants. **Timing **is a vital factor in the treatment of acetaminophen toxicity. Doctors try to start treatment of acetaminophen overdose **within eight hours of ingestion** to achieve the best possible outcome for the patient. Most patients survive acetaminophen toxicity with supportive care such as intravenous fluids and anti-nausea medication, activated charcoal (if used within one hour after ingestion), and antidotal therapy, including N-acetylcysteine (Acetadote®) with either a 21-hour IV regimen or a 72-hour oral regimen. **For patients who fail the above therapies and develop liver failure, liver transplantation may be the only treatment option.** The clinical presentation of an acetaminophen-poisoned patient can be categorized into **four stages**: **Stage** **Timeframe** **Symptoms** ----------- --------------- -------------------------------------------------------------------------------------------------------------------- **1** 0-24 hours May be **asymptomatic **or have **non-specific **symptoms (nausea/vomiting, malaise, pallor, diaphoresis) **2** 24-48 hours Onset of **hepatic injury**; LFTs increase (AST most sensitive marker), hepatic encephalopathy, metabolic acidosis **3** 72-96 hours Fulminant **hepatic failure, **encephalopathy, coma, hemorrhage (rare), hepatorenal syndrome, death **4** \>96 hours **Recovery phase, **hepatic regeneration, normalization of AST, ph, PT/INR, lactate To avoid accidental overdose, the following strategies are recommended: - - - Non-opioid Analgesics - Part 2 **NSAIDs** **Non-steroidal anti-inflammatory drugs** (NSAIDs) are medicines that are widely used to relieve pain, reduce inflammation, and bring down a high temperature. NSAIDs work by inhibiting the activity of cyclooxygenase enzymes (the COX-1 and COX-2 isoenzymes), inhibiting prostaglandin synthesis. COX-1 produces prostanoids for gastric epithelial cytoprotection and for hemostasis, while COX-2 produces prostanoids involved in inflammation and possibly in cancer. Both COX-1 and COX-2 can contribute to inflammation and pain. COX-1 and COX-2 are both formed from arachidonic acid. The effects of COX-1 and COX-2 are illustrated below.  There are two general types of NSAIDs available: **non-selective** and COX-2 **selective**. - Most NSAIDs are non-selective and inhibit the activity of both COX-1 and COX-2. While reducing inflammation, these NSAIDs also inhibit platelet aggregation and increase the risk of gastrointestinal ulcers and bleeds. - COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis, and some of these agents substantially increase the risk of heart attack. Newer NSAIDs have been developed targeting COX-2 specifically to avoid GI side effects. Click for more about considerations for the administration of NSAIDs: **Therapeutic use\ **As a result of their anti-inflammatory, antipyretic, and analgesic effects, NSAIDs are often used to relieve symptoms of headaches, painful periods, sprains and strains, colds and flu, coronavirus (COVID-19), and fever in children. They are a first-line analgesic for inflammatory musculoskeletal injuries and disorders, such as rheumatoid arthritis, that can cause long-term pain. NSAIDs are appropriate for mild to moderate pain, or as an adjunct in the treatment of severe pain, but are not typically recommended for chronic use due to their adverse effects. A table of medication with numbers and letters Description automatically generated with medium confidence **Dosage and Administration\ **There are a number of NSAIDs available on the market, either as prescription or OTC. Dosing depends on the drug's potency and half-life. Most are available orally. Only ketorolac is available intravenously in the United States. More examples are in the table below, sourced from Katzung et al. (2022). **Adverse Effects** Although NSAIDs are commonly used, they're not suitable for everyone and can sometimes cause major side effects. These effects include: - Nausea, diarrhea, abdominal pain, gastric ulcers, GI bleed - Inhibition of platelet activation, increased bruising, bleeding - Salt and water retention, edema, hyperkalemia - Coronary artery disease (MI), stroke, thrombosis **Contraindications** - - - **Warnings/Precautions/Risks\ Asthma** NSAIDs can cause bronchospasm. In general, NSAID-induced bronchospasm develops within 30 to 180 minutes (sometimes up to 24 hours) after drug ingestion, possibly precipitating an asthma exacerbation. **Cardiovascular risk** All NSAIDs can contribute to cardiovascular disease, primarily through fluid retention. Rofecoxib (Vioxx®), a selective COX-2 inhibitor, was withdrawn from the market due to the significant increase in cardiovascular events. **Class effects** - - - - **Bleeding risk** The reduction in protective prostaglandins can cause: - - If prolonged NSAID use is necessary, measures can be taken to minimize the gastrointestinal symptoms and bleeding risk. A proton pump inhibitor can be used to decrease acid and ulceration, and misoprostol, a prostaglandin analog, can be used to help with target prostaglandin regeneration. Some NSAIDs are also available as enteric coated so they are absorbed in the intestine, helping to decrease the effects on the stomach mucosa. **Kidney dysfunction** - - - The mechanism of kidney dysfunction is demonstrated in the image adapted from Katzung et al. (2022) below. As prostaglandins dilate the afferent arteriole, blocking COX-1 with and NSAID inhibits prostaglandin synthesis leading to vasoconstriction of the afferent arteriole, and decreased blood flow to the glomerulus leading to decreased glomerular filtration rate.  **Pregnancy and Lactation\ **NSAIDs have some special considerations during pregnancy and lactation: - - - - **Drug Interactions** - - - - - - -   **Types of NSAIDS** There are many types of non-prescription (OTC) and prescription NSAIDs. **Ibuprofen** Ibuprofen can treat a range of conditions including post-surgical pain and pain from inflammatory diseases such as rheumatoid arthritis. It is available OTC and by prescription. It is also commonly used with OTC combination products for pain and cough/cold remedies. Brand names: Motrin® Advil® Dosage: Typically 200--400mg orally every 4--6 hours for pain, can give up to 800mg/dose Max of 3200mg/day IV formulation no longer readily available due to availability of ketorolac IV. **Aleve** Naproxen is commonly used to treat back pain, strained muscles, and lower back pain. It is available OTC and by prescription.  **Brand names:**  - - - **Dosage: ** - **Ketorolac** Ketorolac is used for the short-term treatment of moderate to severe pain requiring analgesia at the opioid level. It is usually used before or after medical procedures, or after surgery. It is primarily administered intravenously and is only available as a prescription.  **Brand names:**  - - **Dosage:** - - - - **Dose adjustments:** - - **Meloxicam** Meloxicam is used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is primarily taken orally. It is recommended that it be used for as short a period as possible and at a low dose. It is available as a prescription.  Meloxicam can be potentially useful for longer-term use due to COX-2 selectivity and once-daily dosing.  **Brand names: ** - **Dosage: ** - **Celecoxib** Celecoxib is a COX-2 inhibitor. It is used to treat pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It is available by prescription.  Due to its selectivity for COX-2, there is an increased risk of cardiovascular events associated with use --- contraindicated for use after CABG surgery.  **Brand names:**  - - **Dosage:**  - **Aspirin** Aspirin, also known as acetylsalicylic acid (ASA), is used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Aspirin's mechanism of action is thought to be due to decreased production of prostaglandins and thromboxane A2 (TXA2), which is required for platelet aggregation. It is different from other NSAIDs due to its irreversible inactivation of the cyclooxygenase (COX) enzyme.  Aspirin is available as oral and rectal formulations, and enteric-coated tablets are also available to reduce adverse gastrointestinal side effects. Much higher doses of aspirin are required for analgesia and antipyretic effects compared to antiplatelet effects. It can cause Reye's syndrome in children younger than 12 years of age. **Dosage: ** - - - **Adjuvant Analgesics** **Adjuvant analgesics** (or co-analgesics) are drugs that have a clinical use other than pain, but are used as an analgesic in selected circumstances. Adjuvant drugs can be used to enhance the effects of pain medications, treat concurrent symptoms, and provide analgesia for other types of pain. Adjuvants commonly used to enhance the effects of pain medications include: - - - - - **Therapeutic Use ** Depending on the kind of pain, there are several different types of adjuvant analgesics. The ideal combination of medications varies greatly from one person to the next, even among people with the same condition. **Neuropatic Pain ** Neuropathic pain is typically harder to treat than nociceptive pain. First- and second-line adjuvant analgesic medications that have data supporting their use can be used to treat neuropathic pain: **First-line agents** - - - - - - - - - **Second-line agents** - - - **Topical Agents** Topical agents are popular adjuvant choices for neuropathic pain, arthritis, fibromyalgia, CRPS, and other conditions that cause muscle or nerve pain. They\'re also used for injuries such as sprains. These medications are applied directly to the skin and absorbed into the bloodstream. - - - - - - - - - **Musculoskeletal Pain** Adjunct analgesics are used to treat musculoskeletal pain associated with strain, repetitive movements, trauma, immobility, and overuse. They are typically used in the short term and can lead to dizziness, sedation, and hypotension.  - - - - - - - - **Migraines** Migraine is a common **neurological pain condition** that has significant effects on the brain and consequently on behaviors associated with repeated migraine attacks. It can be defined as a primary headache of varying intensity, often accompanied by aura, photophobia (light sensitivity), phonophobia (sound sensitivity), and/or nausea (at times vomiting).  Migraines may be caused by a hereditary susceptibility of the brain and various environmental triggers. These triggers include hormonal changes, certain food and drink, stress, exercise, and sensory stimuli. Migraines are triggered due to a dysfunction of the sensory control system in the thalamus and brainstem. This leads to an activation of cells in the trigeminal nucleus and a release of vasoactive peptides. The neurotransmitters serotonin and dopamine also appear to play a role. **Diagnosis** A full neurologic exam is required to diagnose a patient as suffering from migraines. According to the International Headache Society, migraine diagnosis requires that a patient experience at least five attacks that fulfill the following criteria: 1. Headache attack lasting 4--72 hours 2\. At least two out of four features: - - - - 3\. At least one of the following features: - - **Management** Management of migraines can take the form of pharmacological and non-pharmacological routes. +-----------------------------------+-----------------------------------+ | **Non-Pharmacologic** | **Pharmacologic** | +===================================+===================================+ | Non-pharmacologic routes include: | Pharmacologic routes include: | | | | | - - - - | **- Abortive therapy** is used to | | | stop a migraine after it has | | | started;  however, patients can | | | experience "medication overuse | | | headache" when used too | | | frequently. | | | | | | \- For patients who experience | | | more than five migraine attacks | | | per month, **preventive | | | therapy** can be considered. | | | Therapy needs to be | | | individualized as the same | | | medication may not work for | | | everyone. | +-----------------------------------+-----------------------------------+ **Pharmacologic Treatment** Preventive and pain-relieving medication can help manage migraine headaches. There are a variety of medications that could be prescribed to treat migraines. These include NSAIDs and Excedrin® (acetaminophen 250mg, aspirin 250mg, caffeine 65mg), which are available OTC. NSAIDs are often used in combination with triptans, which are discussed more below. Antiemetics, such as metoclopramide and prochlorperazine, can be used for the nausea associated with migraines. Opioids have little to no role in the treatment of migraines. Any pharmacologic treatment used for abortive therapy will be most effective when taken early during an attack. Let's take a look at migraine-specific therapy in more detail. **Fioricet®, Fiorinal®\ ** Fioricet^®^ (Butalbital 50mg, acetaminophen 300mg, caffeine 40mg +/- codeine 30mg) and Fiorinal^®^ (Butalbital 50mg, aspirin 325mg, caffeine 40mg) are both used to treat migraine headaches, but are not recommended as first-line treatment. They are classified as Schedule III controlled substances. Both medications contain butalbital and caffeine, but Fioricet^®^ also has acetaminophen whereas Fiorinal^®^ contains aspirin. Unlike acetaminophen, aspirin also treats inflammation and swelling.  **Dose:**  - - **Adverse reactions:** - - - **Cautions:** - - **Antiemetics/Prokinetics\ **Antiemetics given orally, such as metoclopramide and prochlorperazine, can be used to treat nausea associated with acute migraine headache. These medications act as antiemetics mainly because they are dopamine receptor antagonists. In addition, they have some effect in reducing migraine headache pain.    **Mechanism of action: ** - - - - **Dose:** - **Adverse effects: ** - - - **Dose:** - **Adverse effects: ** - - - **Triptans** Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. Triptans are selective agonists for 5-HT1D and 5-HT1B receptors. They're thought to work by reversing the changes in the brain that may cause migraine headaches. They cause the blood vessels around the brain to narrow (contract). This reverses the widening of blood vessels that's believed to be part of the migraine process. Triptans are available as tablets, injections, and nasal sprays. Proposed mechanisms: - - - **Class effects:** - - - **Drug interactions:** - - - Below is a table from Katzung et al. (2022), showing the available triptans, including route and doses. It is important to note that one triptan may not work as well for one patient and another one could be trialed instead.  A table with text and images Description automatically generated **Ergot Alkaloids** Ergot alkaloids are less commonly used for the treatment of acute migraine headaches and include ergotamine and dihydroergotamine, both of which act by causing vasoconstriction of the carotid artery beds. They are non-selective serotonin receptor agonists that inhibit trigeminovascular inflammation. Ergot alkaloids can be administered via IM, subcutaneous, IV, and others. Examples of ergot alkaloids include Dihydroergotamine (DHE) and Migranal^®^ (Intranasal).  **Dose: ** - - - **Adverse effects:** - - - - **Contraindications: ** - - - **Cautions:** - - **Preventive Therapy** Indications for preventive therapy: Frequent or long-lasting migraine headaches. Migraine attacks that cause significant disability or diminished quality of life despite appropriate acute treatment. - - - - Below is a table, sourced from Silberstein et al. (2012), of medications that have some data suggestive of their efficacy in preventing migraine headaches.  **CGRP Antagonists** Calcitonin gene-related peptide (CGRP) receptor antagonists are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor (CGRPR). Several monoclonal antibodies, which bind to the CGRP receptor or peptide, have been approved for both abortive and preventive therapy of migraines. CGRP is one of the inflammatory neuropeptides that are elevated during migraines. By blocking these receptors, patients see decreased effects. There are now six FDA-approved anti-CGRP medications for use in the United States. Those for preventive treatment that are administered by injection (with the exception of Vyepti® which is IV administered) include: - - - - The remaining anti-CGRP medications are for acute treatment and orally administered: - - **Opioid Analgesics** Opioids are a group of analgesic agents that work by interacting with opioid receptors, found principally in the central and peripheral nervous system and the gastrointestinal tract, to inhibit the perception of pain and boost feelings of pleasure. There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta), coupled to intracellular mechanisms via G-proteins. Opioids can act at these receptors as agonists, antagonists, or partial agonists. Opioid agonists bind to G-protein coupled receptors to cause cellular hyperpolarization and a reduction in neuronal excitability. The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist.   **Therapeutic Effects** - - - - - - - - - **Therapeutic Use** Opioid therapy should be considered only if the expected benefits of their use outweigh the associated risks, including respiratory depression and opioid dependence. To minimize these risks the following prescriptive guidelines can be followed: - - - **Adverse Effects** - - - - - - - - - - - **Severe Adverse Effects** - - - - - - - - - - - - **Contraindications and Precautions** Contraindications - - - Warnings/precautions - - - - - - - **Pregnancy and Lactation** Research indicates that a fetus can become dependent on opioids in utero, leading to neonatal withdrawal syndrome. Morphine and clonidine are required treatments for withdrawal syndrome. The symptoms of this syndrome include: - - - - - -   Lactation - **Structural Classes** The opioid structural class is based on the **structure of the opioid**, which is important for adverse effects and allergies.  - - - - - - - - - - - - **Functional Classes** The opioid functional class is based on **how the opioid functions** as an agonist, partial agonist, or antagonist. - - - - - - - - - - - - - - - ### **Summary of General Principles of Pain Management** - **Setting Expectations:** - Treating pain does not mean achieving a pain score of zero out of 10. - The goal is to minimize pain while improving quality of life and enabling patients to maintain important activities. ### ### Non-Opioid Analgesics 1. **Acetaminophen:** - **Key Features:** - Used for mild to moderate pain. - Not anti-inflammatory, distinguishing it from NSAIDs. - **Safety Considerations:** - Maximum dose: 4 grams per day. - Exceeding this dose can lead to acute liver failure. - Acetaminophen overdose (intentional or unintentional) is the primary cause of acute liver failure. 2. **NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):** - **Mechanism of Action:** - Inhibit COX-1 and COX-2 enzymes, reducing prostaglandin synthesis. - **Examples:** - Ibuprofen, naproxen, and aspirin. - **Side Effects:** - Kidney damage. - Gastrointestinal bleeding. ### ### Adjuvant Analgesics - Primarily used for **neuropathic pain**. - Include agents such as: - Anti-seizure medications. - Muscle relaxants. - Should be used in specific cases for certain patients. ### ### Migraine-Specific Medications 1. **Classes of Medications:** - **Butalbital combinations.** - **Triptans:** - Act on serotonin 1D and 1B receptors. - Modulate CGRP and cause vasoconstriction and decreased inflammation. - **CGRP Antagonists:** - Directly decrease CGRP, an inflammatory neuropeptide elevated during migraines. 2. **Other Agents:** - **Ergot Alkaloids:** - Act similarly to triptans on serotonin receptors to reduce inflammation and cause vasoconstriction. **Types of Opioids: Codeine (C-II)** There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. **Codeine (C-II)** Codeine is used to treat **mild to moderate pain**. It comes in tablet form and is the main ingredient in prescription-grade cough suppressants. Tylenol \#3, a popular painkiller, is codeine combined with acetaminophen. Codeine is converted by CYP2D6 into morphine, which is important for much of its analgesic effect. A diagram of a chemical structure Description automatically generated **Dosing and Administration** - - **Pharmacokinetics** - - - **Metabolism** - - - - **Excretion** - **Product Availability** Codeine (C-II) - - Codeine with acetaminophen - - - - - - - **Warning and Precautions** - - **Types of Opioids: Morphine Sulfate (C-II)** There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. **Morphine Sulfate (C-II)** Morphine is one of the **most commonly prescribed** opioids. It is used for post-operative pain, chronic pain, and to ease pain associated with dying. It is available in many formulations including tablet, capsule, solution, and injection. It is important to know that both active and inactive metabolites are potentially toxic. Therefore adverse effects are most likely to occur in those who are elderly or with renal dysfunction and/or hemodialysis. It is important to monitor for adverse effects closely and consider using a different opioid such as hydromorphone or oxycodone. It is recommended to avoid long-acting (daily) formulations in high-risk populations. **\ Dosing and Administration (oral, opioid naïve)** - -   **Pharmacokinetics** - - - - - - -  Types of Opioids: Hydromorphone (C-II) ======================================= There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. **Hydromorphone (C-II)** Hydromorphone is a **very potent **opioid. It is typically reserved for pain refractory to other opioids such as morphine or codeine. It is also a good alternative for those with renal dysfunction as its clearance is less reliant on good kidney function. **Dosing and Administration (ral, opioid naïve)** - - **Availability** - - - **Pharmacokinetics** - - - - - - - - - - - **Types of Opioids: Hydrocodone (C-II)** ======================================== There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. Hydrocodone (C-II) ------------------ Hydrocodone is not typically used on its own and is most commonly prescribed in combination with acetaminophen or aspirin. It is commonly used after dental procedures. **Dosing and Administration** - - - **\ Formulations** Combination with acetaminophen - - Long-acting - - **^\ ^Pharmacokinetics** - - - - - - **Types of Opioids: Oxycodone (C-II)** ====================================== There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. Oxycodone (C-II) ---------------- Oxycodone is a frequently used opioid that is generally better tolerated than morphine. It is only available in oral formulations. **Dosing and Administration (ral, opioid naïve)** - - **\ Availability** - - - **\ Pharmacokinetics** - - - - - - - - - -  \ **Combination Products** - - - - - - - - **Types of Opioids: Hydrocodone (C-II)** ======================================== There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. Hydrocodone (C-II) ------------------ Hydrocodone is not typically used on its own and is most commonly prescribed in combination with acetaminophen or aspirin. It is commonly used after dental procedures. **Dosing and Administration** - - - **\ Formulations** Combination with acetaminophen - - Long-acting - - **^\ ^Pharmacokinetics** - - - - - - **Types of Opioids: Fentanyl (C-II)** ===================================== There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. Fentanyl (C-II) --------------- Fentanyl is **extremely potent** and should not be used for opioid naïve patients. It is typically reserved for those in chronic pain, including cancer patients. Calculating the dose can be challenging as the potency changes from one formulation to another cannot be converted 1:1. **\ Formulations** - - - - - - - - - - **\ Pharmacokinetics** - - - - - - - **\ Conversion** Fentanyl requires a very specific conversion from other opioids. The table below, sourced from Lexicomp, Inc. (2015), can be used for conversion.  **Types of Opioids: Methadone & Buprenorphine** =============================================== There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. Methadone (Dolophine®, C-II) ---------------------------- Methadone can be used for pain management and is typically used for chronic pain in that capacity. Primarily it is used for the **treatment of opioid use disorder** for which the dosing is very different and will be discussed in the next module. - - - - - - - - - - Buprenorphine (C-III) --------------------- Buprenorphine is a partial agonist and thus has an analgesic ceiling. Because of this, it has a lower potential for abuse. It is also used for the treatment of opioid use disorder and is highly regulated. Buprenorphine comes in several formulations, including: - - - - **Types of Opioids: Tramadol** ============================== There are many types of prescribed opioids that are known by several names. The different types of opioids are prescribed in different strengths and administered in various forms, depending on the patient, the situation, and the type and level of pain. Let's look at these types in more detail. Tramadol (Ultram®, C-IV) ------------------------ Tramadol is a strong pain medication used to treat **moderate to severe pain **that is not being relieved by other types of pain medicines. It is a centrally-acting synthetic analgesic with multiple mechanisms, including: - - - - Despite the multiple mechanisms, it is a less efficacious opioid. **\ Metabolism** - - - **\ Excretion** - **\ Prescribing** - - - - All - Some:  - Some:  - - - **Opioid Conversion** ===================== Patients may need to be switched from one opioid to another based on their needs.  For example, moving from an IV dose for inpatient use to an oral dose for outpatient use. Equianalgesic Conversion ------------------------ This type of conversion is used because a patient may develop tolerance to the opioid they are on, necessitating higher doses. However, the patient will not have the same tolerance to a different opioid and the dose should be reduced for this consideration. Follow these steps to calculate equianalgesic dose between two opioids: 1. 2. 3. 4. 5. Below is a table, sourced from the Yale New Haven Hospital Opioid Equianalgesic Chart (2008), showing the equivalent dose, both IV and oral, between different opioid agents.  A table with numbers and letters Description automatically generated Below is a 2014 Duragesic package insert table detailing the conversion between oral morphine and a fentanyl patch. If patients are on a different opioid than morphine, such as oxycodone, oxycodone should be converted to morphine and then morphine converted to fentanyl.  Example Scenario ---------------- Let's examine what opioid conversion might look like in a real-world scenario. JM is a 55-year-old with colorectal cancer and COPD and has been taking extended-release morphine 30mg every 8 hours with immediate release morphine 10mg every 4--6 hours as needed for breakthrough. Typically JM takes two doses of breakthrough medication throughout the day. They express frustration that they have to take their long-acting medication three times a day and ask to be switched to a longer-acting medication. You decide to convert to an oxycodone regimen. What would be an appropriate dosing regimen for JM? **Step 1: Calculate 24-hour requirements\ ** - - **Step 2: Account for cross-tolerance (\~25-50%)\ ** - - **Step 3: Convert to oxycodone daily dose\ ** - - - **Step 4: Select dosing regimen based on tablet strengths available\ ** - - ### **Opioids: Overview and Key Considerations** 1. **Commonly Used Opioids:** - Morphine - Oxycodone - Fentanyl - Hydromorphone - Methadone 2. **Appropriate Use:** - Reserved for **severe pain** due to their high risk of addiction. - Classified as **Schedule II controlled substances** in the United States. 3. **Effectiveness:** - All opioids are equally effective but vary in **potency** (i.e., the dose required to achieve the same level of pain relief). 4. **Key Adverse Effect:** - **Respiratory depression** is the primary adverse effect to monitor, as it is the leading cause of death from opioid overdose. 5. **Prescribing Considerations:** - Assess **why** the patient is using the opioid. - Set clear expectations for **duration of use** and plan for reassessment to determine ongoing need. **Modules Objectives** ### 1. Differences Between Nociceptive and Neuropathic Pain - **Nociceptive Pain:** - Caused by **tissue damage** and detected by nociceptors. - Can be **somatic** (e.g., muscle or joint pain, usually localized) or **visceral** (e.g., organ pain, less localized). - Treated with NSAIDs, acetaminophen, or opioids. - **Neuropathic Pain:** - Caused by **nerve damage** or dysfunction. - Characterized by hypersensitivity (e.g., hyperalgesia, allodynia). - Examples: diabetic neuropathy, postherpetic neuralgia. - Treated with adjuvant therapies like anticonvulsants (gabapentin, pregabalin) and antidepressants (amitriptyline, duloxetine). ### 2. Comparison of Analgesic Medication Classes - **Non-Opioid Analgesics:** - **Acetaminophen:** Effective for mild to moderate pain; not anti-inflammatory; risk of liver toxicity. - **NSAIDs:** Anti-inflammatory and analgesic; risk of GI bleeding and renal impairment. - **Opioids:** - Used for severe pain; highly effective but associated with addiction and respiratory depression. - Includes morphine, oxycodone, fentanyl, and hydromorphone. - **Adjuvant Analgesics:** - Includes anticonvulsants, antidepressants, and topical agents. - Primarily used for neuropathic pain or as an adjunct in multimodal pain management. ### 3. Selecting a Candidate for Migraine Prophylaxis and Analgesic Regimen - **Appropriate Candidate for Migraine Prophylaxis:** - Frequent or disabling migraines (\>5 per month). - Contraindication to acute therapies or risk of medication overuse. - Medications include beta-blockers (e.g., propranolol), CGRP antagonists (e.g., erenumab), or anticonvulsants (e.g., topiramate). - **Example Regimen for Prophylaxis and Acute Pain Relief:** - **Prophylaxis:** Propranolol 20 mg BID or erenumab 70 mg monthly. - **Acute Relief:** Sumatriptan 50 mg at migraine onset and repeat in 2 hours if necessary. ### 4. Role of Non-Opioid Analgesics in Pain Management - First-line therapy for mild to moderate pain. - Used alone or as adjuncts to reduce opioid requirements. - Preferred due to fewer risks of dependence and overdose. - Examples: acetaminophen for osteoarthritis and NSAIDs for inflammatory conditions. ### 5. Review of Opioid Classes and Specific Medications - **Phenanthrenes:** Includes morphine, codeine, oxycodone, and hydromorphone. - **Phenylpiperidines:** Includes fentanyl and meperidine. - **Phenylheptanes:** Includes methadone. - **Functional Classes:** Full agonists (e.g., morphine), partial agonists (e.g., buprenorphine), antagonists (e.g., naloxone). ### 6. Calculating an Equianalgesic Dose - **Steps for Conversion:** 1. Determine the total 24-hour opioid requirement. 2. Use an equianalgesic table to convert to a new opioid. 3. Adjust for cross-tolerance (reduce dose by 25--50%). 4. Divide into long-acting and breakthrough doses. - **Example Calculation:**\ Converting from morphine 90 mg/day to oxycodone: 1. Morphine to oxycodone ratio: 30 mg morphine = 20 mg oxycodone. 2. Total oxycodone dose: 60 mg/day. ### 7. Application to a Patient Case - **Case Scenario Example:** - Patient on morphine 90 mg/day with inadequate pain control. - Convert to oxycodone with cross-tolerance adjustment: - Morphine equivalent: 90 mg/day × 0.67 = 60 mg/day oxycodone. - Regimen: Oxycodone ER 20 mg BID + Oxycodone IR 10 mg Q6H PRN for breakthrough. ### Answers to Questions #### 1. What is the importance of multimodal pain management? Multimodal pain management uses a combination of pharmacologic and non-pharmacologic therapies to target different pain pathways, enhancing pain relief while minimizing the risks associated with any single treatment, especially opioids. It promotes better outcomes by reducing opioid use and its associated side effects, such as dependence and tolerance​. #### 2. How do you feel about using opioids in your practice? The decision to use opioids must balance the benefits of effective pain management with the risks of addiction, dependence, and overdose. It is critical to adhere to guidelines, use the lowest effective dose, and incorporate non-opioid treatments wherever possible to ensure patient safety​. #### 3. What are the ethical considerations for prescribing controlled substances? Ethical considerations include: - Prescribing only for legitimate medical purposes. - Staying within the prescriber\'s scope of practice. - Avoiding unnecessary prescriptions that could lead to abuse or diversion. - Working collaboratively with pharmacists to ensure responsible use​. #### 4. What are the legal standards you have discovered for prescribing controlled substances in your state? The specific legal standards may vary by state, but general federal guidelines include: - Schedule II substances require a written prescription with no refills allowed. - Schedule III-V substances can have up to five refills within six months. - Prescribers must be registered with the DEA and ensure prescriptions include all required elements, such as the DEA number​. State laws may add stricter regulations, which should always be followed. #### 5. In the event that a patient of yours becomes addicted to their prescription medications, what is the appropriate form of treatment? The treatment involves: - **Detoxification**: Gradual tapering of the medication under medical supervision to minimize withdrawal symptoms. - **Medication-Assisted Treatment (MAT)**: Use of drugs like buprenorphine, methadone, or naltrexone to manage dependence. - **Counseling and Behavioral Therapy**: Addressing the psychological aspects of addiction through therapy and support groups. - Referral to specialized addiction treatment programs as needed​. ### Answers to Questions #### 1. Explain the differences between nociceptive and neuropathic pain. - **Nociceptive Pain**: - Caused by tissue damage, detected by nociceptors. - Subtypes: - **Somatic Pain**: Localized, often described as gnawing or sharp (e.g., muscle or joint pain). - **Visceral Pain**: Less localized, associated with internal organs, described as cramping or squeezing. - Treated with NSAIDs, acetaminophen, or opioids​. - **Neuropathic Pain**: - Caused by nerve damage or dysfunction. - Characterized by hypersensitivity (e.g., hyperalgesia, allodynia). - Examples: diabetic neuropathy, postherpetic neuralgia. - Treated with adjuvant therapies such as anticonvulsants (gabapentin) or antidepressants (amitriptyline)​. #### 2. Compare and contrast classes of analgesic medications. - **Non-Opioid Analgesics**: - **Acetaminophen**: Used for mild to moderate pain; lacks anti-inflammatory effects; risk of liver toxicity. - **NSAIDs**: Anti-inflammatory and analgesic; risks include GI bleeding and renal impairment​. - **Opioids**: - Used for severe pain; highly effective but pose risks of addiction and respiratory depression. - Examples: morphine, oxycodone, hydromorphone​. - **Adjuvant Analgesics**: - Used primarily for neuropathic pain. - Examples: anticonvulsants (gabapentin), antidepressants (duloxetine), and topical agents (lidocaine)​. #### 3. Select an appropriate candidate for migraine prophylaxis and create an analgesic regimen. - **Candidate for Prophylaxis**: - Frequent migraines (\>5 per month) or significant disability. - Contraindications to acute therapies or risk of medication overuse​. - **Regimen**: - **Prophylaxis**: Propranolol 20 mg BID or erenumab 70 mg monthly. - **Acute Relief**: Sumatriptan 50 mg at onset, repeat after 2 hours if necessary​. #### 4. Identify the role of non-opioid analgesics in the management of pain. - **Role**: - First-line treatment for mild to moderate pain. - Reduce opioid requirements in multimodal therapy. - Safer long-term profile compared to opioids, with fewer risks of dependence and overdose. - Examples: - Acetaminophen for osteoarthritis. - NSAIDs for inflammatory conditions​. #### 5. Review the various opioid classes and specific opioid medications. - **Classes**: - **Phenanthrenes**: Morphine, codeine, oxycodone, hydromorphone. - **Phenylpiperidines**: Fentanyl, meperidine. - **Phenylheptanes**: Methadone​. - **Functional Classes**: - Full agonists (e.g., morphine). - Partial agonists (e.g., buprenorphine). - Antagonists (e.g., naloxone)​. #### 6. Calculate an equianalgesic dose of an opioid regimen when converting to another regimen. - **Example Conversion**: - Patient on 90 mg/day oral morphine wants to switch to oxycodone. - Morphine to oxycodone ratio: 30 mg morphine = 20 mg oxycodone. - **Steps**: 1. Calculate total daily dose: 90 mg morphine = 60 mg oxycodone. 2. Adjust for cross-tolerance (\~25% reduction): 60 × 0.75 = 45 mg/day oxycodone. 3. Prescribe: Oxycodone ER 20 mg BID + 5 mg IR Q6H PRN​. #### 7. Apply knowledge of analgesics to a patient case. - **Case**: - A patient on morphine 90 mg/day with inadequate pain control switches to hydromorphone. - **Steps**: 1. Calculate daily morphine dose: 90 mg. 2. Morphine to hydromorphone ratio: 30 mg morphine = 7.5 mg hydromorphone. 3. Adjust for cross-tolerance (\~50% reduction): 90 × 0.5 × (7.5/30) = 11.25 mg/day hydromorphone. 4. Prescribe: Hydromorphone ER 4 mg BID + IR 2 mg Q4H PRN for breakthrough pain​.