Achieving Adequate Pain Management, Pharmacological Indications

Basics of Pain Management

Researchers in the Korean Journal of Pain note, “the three steps for analgesic administration and pain management are pain relief at night, bed rest in the daytime, and active movement during daily life. In addition, the principle of polypharmacy is focused on increasing therapeutic effects (analgesia) while reducing adverse reactions (ADRs) based on the source of the pain.”

According to the Korean Journal of Pain, treating pain pharmacologically begins with understanding the source, type, or class of pain. The journal notes that the two main pain types are emotional and sensory. Under sensory pain, there are two more categories: nociceptive and neuropathic pain.

Nociceptive pain can be somatic or visceral. Somatic pain can be further divided into superficial or deep. The Korean Journal of Pain recommends non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, acetylsalicylic acid, or steroids for all types of somatic pain. On the other hand, the journal notes that visceral pain responds best to opioids.

Neuropathic pain has positive and negative symptom categories. Positive symptoms are best treated with anticonvulsants, while negative symptoms are treated with antidepressants. 

In an article published in Pain Management, researchers note that non-pharmacological approaches to pain management include cognitive behavioral therapy (CBT), physical activity, physical therapy, and acupuncture. These methods may be considered for patients who do not respond to pharmacological treatments, do not want pharmacological therapies, or cannot be treated with medications due to concurrent or historical medical conditions.

Types of Pharmacological Pain Management

According to a StatPearls textbook, there are multiple different classes of analgesics, including the following:

• acetaminophen (APAP)
• NSAIDs
• antidepressants
• anticonvulsants, also known as antiepileptics
• local anesthetics
• opioids

APAP

According to the EMRA, APAP is antipyretic and analgesic. APAP is a noncompetitive inhibitor of COX-3, a COX-1 splice variant enzyme, in the brain and spinal cord. This prevents pain perception. In the article, Koehl notes, “APAP easily crosses the blood-brain barrier and is distributed throughout the central nervous system (CNS), allowing it to reach concentrations in the brain able to inhibit COX-3 enzymatic activity. APAP does not bind directly to the active site on the enzyme but reduces the active form and inhibits its catalytic activity.”

Aside from the central mechanism of action, COX inhibition, APAP is thought to modulate the endogenous cannabinoid system. APAP can be de-acetylated into p-aminophenol and interact with arachidonic acid to make N-arachidinoyl-phenolamine (AM404). This compound can act as a cannabinoid receptor agonist, increasing levels of endogenous cannabinoids.

APA is used for mild to moderate pain and can also be used alongside other agents to manage severe pain. The EMRA notes that APAP is best and most often used to treat acute pain in emergency settings.

The organization notes that, most commonly, it is administered as a 1,000 mg dose alongside 400 mg of ibuprofen. The EMRA recommends 4,000 mg as a maximum daily dose of APAP; however, patients with a history of liver disease should not exceed 3,000 mg as side effects include liver toxicity, necrosis, nausea, and vomiting.

While good at managing pain perception, APAP use can be associated with various adverse side effects, including gastrointestinal issues. COX-1, when uninhibited, maintains gastrointestinal (GI) mucosa, renal blood flow, and platelet aggregation.

NSAIDs

According to an article published in the Korean Journal of Pain, NSAIDs are anti-inflammatory, analgesic, and antipyretic. They are an effective way to treat pain; however, pain relief is accompanied by adverse gastrointestinal events.

The EMRA states that, like APAP, NSAIDs inhibit COX-1. However, unlike APAP, NSAIDs are competitive inhibitors of COX-2 and COX-1. This inhibition prevents the generation of prostaglandins that mediate inflammation or pain. Reduced prostaglandin levels also may minimize swelling and redness.

According to the EMRA, traditional NSAIDs are non-selective competitive inhibitors of COX-1 and COX-2. Traditional NSAIDs may include aspirin, ibuprofen, naproxen, and ketorolac. Conversely, some NSAIDs have a higher affinity for COX-2, including indomethacin, meloxicam, and diclofenac.

When blocking COX-1, NSAIDs can cause nausea, vomiting, gastric ulceration, bleeding, and kidney injury, as COX-1 is typically responsible for mediating GI, renal, and platelet concerns. With that in mind, many providers may opt for the second class of NSAIDs with a higher affinity for COX-2 to improve the gastric safety profile of the medications. These benefits come with downsides because COX-2 is associated with myocardial infarctions, stroke, and heart failure.

NSAIDs are often used to manage mild to moderate pain and reduce inflammation. NSAIDs are not recommended for patients over 50 with a family history of GI disease, pregnant individuals in the third trimester, those with inflammatory bowel disease, or those who have undergone gastric bypass surgery. Choosing which NSAIDs to use is typically based on the patient, medical history, source of pain, and other factors.

Opioids

Another class of pain management medications is opioids. Opioids are most commonly used for patients with severe acute pain and end-of-life or cancer-related pain. This class of drugs is highly controversial as it is associated with high addiction rates and other adverse outcomes.

StatPearls notes that opioids are a broad classification for many different medications, and the mechanism of action may vary slightly based on the type of opioid. However, most opioids are considered mu agonists. Opioids block calcium channels on the presynaptic membrane and increase the activity of potassium channels on the postsynaptic membrane. Blocking calcium channels can prevent the release of certain neurotransmitters for pain perception. Additionally, increased activity of postsynaptic potassium channels hyperpolarizes the cell, preventing neurotransmission.

Pain Management says opioids can cause constipation, nausea, vomiting, impaired cognition, and respiratory depression. Continued opioid use is also associated with suppressed hypothalamic, pituitary, gonadal, and adrenal hormones.

Pain Management recommends, “Opioids should be prescribed only with clearly defined therapeutic goals, after weighing the potential positive effects on pain and function against potential risk. The selected agent should be provided on a trial basis initially, starting at a low dose and then titrated slowly.” Researchers in the journal also recommend initial risk assessments before prescribing opioids.

Antidepressants and Anticonvulsants

According to StatPearls, antidepressants prevent the reuptake of serotonin and norepinephrine — sometimes referred to as noradrenaline — which inhibits the central nervous system pathways associated with pain. These medications can treat fibromyalgia and musculoskeletal pain and manage migraines and tension headaches.

Side effects of antidepressants may include altered cognition, headache, suicidal thoughts, weight gain, nausea, dizziness, or abdominal pain. However, the probability of experiencing one of these side effects can vary depending on the medication and the patient’s medical history.

Antiepileptic medications work by lowering neurotransmitter release or neuronal firing and are most effective in treating neuropathic pain. Antiepileptic drugs bind to certain parts of volage-dependent calcium channels, which are overactive in patients with neuropathic pain, reducing excitability.

Anticonvulsant medications may cause side effects such as dizziness, depression, fever, headache, edema, weight gain, and more.

Local Anesthetics

Additionally, local anesthetics, such as lidocaine, are commonly used for peripheral neuropathic pain. According to StatPearls, “lidocaine stabilizes the neuronal membrane by inhibiting sodium ion channels on the internal surface of nerve cell membranes. Thus, pain conduction through nerve impulses becomes impaired at the site of action, which contributes to the absence of systemic effects.”

Effectively Managing Pain

Adequate pain management involves multiple factors. Pain Management notes that some barriers prevent patients from achieving adequate pharmacological pain relief. Chief of these is a failure to report. Much like migraines, chronic pain is a condition many people do not report to their physicians. This may be due to assumptions about pain with aging.

Pain Management notes, “pharmacotherapy should be considered for all patients with pain that negatively impacts the quality of life. Understanding the pharmacology of all potentially useful agents and patient-specific factors, coupled with ongoing monitoring of therapeutic goals and adverse effects, will greatly help to optimize outcomes. Currently available evidence-based clinical guidelines should be referred to as a means of improving clinical practice.”