Acute and Chronic Pain
N609

Explain pain pathophysiology and the neurotransmitters involved in the facilitation of pain.
Classify pain based on source and chronicity.
Select first-line treatments for a patient with acute or chronic pain.
Compare and contrast the current medication options for the treatment of acute and chronic pain.

Definition
"An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage" (Merskey & Bogduk, 1994).
Pain is subjective, and its intensity varies from patient to patient and from day to day.
Clinicians have a wide array of medications available to assist patients in relieving pain.

Nociceptive: occurs as a result of nerve receptor stimulation following a mechanical, thermal, or chemical insult.
Somatic (associated with muscle, skin, or bone injury)
Visceral (affecting the visceral organs)
Central: pain from multiple sclerosis, spinal cord injuries, migraine, and poststroke syndrome.
Neuropathic: caused by abnormal signal processes in the central nervous system (CNS).
Peripheral: pain from diabetes and postherpetic neuralgia

Inflammatory
A subtype of nociceptive pain that results from the release of proinflammatory cytokines at the site of tissue injury.
Present in acute pain (bruises or infection) and chronic pain (rheumatoid arthritis or osteoarthritis).

A patient complains of pain from a migraine. How would the practitioner classify this type of pain?
A. Central neuropathic pain
B. Peripheral neuropathic pain
C. Inflammatory pain
D. Somatic nociceptive pain

A. Central neuropathic pain
Rationale: Examples of central neuropathic pain syndromes include pain from multiple sclerosis, spinal cord injuries, migraine, and poststroke syndrome. Peripheral neuropathies include pain from diabetes and postherpetic neuralgia. Inflammatory pain may be present in acute pain from bruises or infection and chronically in pain from rheumatoid arthritis or osteoarthritis. Somatic pain is associated with muscle, skin, or bone injury and is often well localized.

Acute
Sudden onset: usually subsides quickly.
Characterized by sharp, localized sensations with identifiable cause.
Chronic
Pain persisting beyond the normal time and despite efforts to diagnose and treat original condition/injury.
Peripheral and central sensitization of pathways occurs.

Cancer-related pain
Pain associated with malignancy that can result from the disease itself or damage to secondary tissue.
Pain secondary to direct tumor involvement of bone, nerves, viscera, or soft tissue.
Chronic noncancer pain
Persistent pain seen in patients not affected by cancer.
Examples include osteoarthritis and fibromyalgia.

Breakthrough pain (BTP)
A transitory pain often seen in conjunction with chronic pain, where moderate-to-severe pain occurs in patients with otherwise well-controlled pain.
True BTP is characterized as brief, lasting minutes to hours, and can interfere with functioning and quality of life.

Transduction
Refers to a process of nociceptor activation due to mechanical, thermal, or chemical injury; nerve endings are activated through the release of various excitatory chemical neurotransmitters.
Transmission
Results in an action potential transmitted via the myelinated A-delta and unmyelinated C fibers, by way of the dorsal root ganglia, synapsing in the dorsal horn of the spinal cord.

Perception
Nociceptive information travels through different areas of the CNS to the brain where the pain is perceived; perception is the end result of the pain transmission to the brain.
Modulation (serotonin and norepinephrine)
Pain modulation occurs at various levels of the CNS; endogenous opioids work through binding of opioid receptors in both the periphery and CNS.

What stage of nociception is occurring when neurotransmitters in the dorsal horn directly or indirectly depolarize the second-order neurons?
A. Transduction
B. Transmission
C. Perception
D. Modulation

B. Transmission
Rationale: During transmission, neurotransmitters in the dorsal horn directly or indirectly depolarize the second-order neurons, facilitating transmission of information to the brain and leading to the perception of pain. During transduction, nerve endings are activated through the release of various excitatory chemical neurotransmitters. Perception is the end result of the pain transmission to the brain. Pain modulation occurs at various levels of the CNS, where endogenous opioids bind opioid receptors in both the periphery and CNS.

Peripheral sensitization
When pain receptors in the periphery are continually stimulated (i.e., untreated acute pain), the threshold for stimulation becomes lowered and increased nerve firing occurs.
Central sensitization
Defined as "an amplification of neural signaling within the CNS that elicits pain hypersensitivity" (Woolf, 2011).

Include neurotransmitters, norepinephrine, serotonin, and histamine, and polypeptides such as bradykinin, prostaglandins, and substance P.
Their role is activating and sensitizing nociceptors and increasing neuronal excitability.
Excitatory amino acids, glutamate and aspartate, along with substance P facilitate activation of second-order neurons in the dorsal horn primarily through activation of the N-methyl-d-aspartate (NMDA) receptors.

Extremely important for determining proper treatments as well as monitoring effectiveness over time.
Self-reporting is the most reliable indicator of pain.
Single-dimension assessment tools include visual analog scale, numerical rating scale, and verbal description scale.
Multidimensional scales include Brief Pain Inventory and Initial Pain Assessment Tool.
The assessment of the patient's pain and the efficacy of the treatment plan should be ongoing and documented.

A practitioner conducting a pain assessment asks the patient "is the pain consistent or intermittent?" What character of pain is the practitioner assessing?
A. Quality
B. Region
C. Severity
D. Temporal pattern

D. Temporal pattern
Rationale: The temporal pattern describes whether the pain is constant or intermittent and if it is associated with movement. Quality describes what the pain feels like (sharp, stabbing, burning). Region refers to the location of the pain. Severity is derived from the pain assessment and reflects the intensity of the pain.

Physical methods (e.g., hot/cold therapy); massage
Patient education (Therapeutic Neuroscience Education)
Coping skills training
Cognitive-behavioral therapy
Transcutaneous electrical nerve stimulation
Acupuncture
Mindful meditation

Injections
Spinal fusion
Percutaneous disc compression
Radiofrequency rhizotomy
Neuromodulatory therapy
Vertebroplasty
Kyphoplasty

Nonopioid analgesics
Acetaminophen
Nonsteroidal anti-inflammatory drugs
Opioids
Morphine and congeners; fentanyl and congeners
Multiple-mechanism analgesics
Opioid antagonist-naloxone

Sedation
Confusion
Respiratory depression
Itching
Nausea/vomiting
Constipation

Antidepressants
Anticonvulsants
Sodium-channel blockers
NMDA-receptor antagonists
Skeletal muscle relaxants
Antispastic agents

Pain is difficult to manage and often needs a multidisciplinary approach to therapy.
Treatment needs to be individualized for each patient, especially when a chronic pain condition exists.
A proper assessment must be performed in order to differentiate the type and chronicity of pain.
Once the type of pain is determined, patient-specific factors should be evaluated in order to choose the appropriate analgesic for pain treatment.

Screen and assess pain in patients with opioid use disorder (OUD).
Develop treatment plans to both alleviate pain and prevent relapse when on medication-assisted treatment.
Monitor the safety and efficacy of pharmacotherapy for pain in OUD.

Relief of pain is the most frequent reason that opioids are abused.
In patients with current or remitted opioid use disorder (OUD) that are experiencing pain, the appropriate management of the pain will help prevent inappropriate use of opioids often obtained from nonmedical sources.

Pain provides both a positive and negative reinforcement of opioid use.
Opioids produce feelings of pleasure primarily due to activation of the ventral tegmental area and subsequent release of dopamine from the nucleus accumbens.
The positive and negative reinforcement of opioids is decreased in chronic pain resulting in the need for higher and more frequent doses.

When assessing pain, patients with OUD should be treated like any other patient.
A thorough assessment should be conducted with type and class of pain identified using subjective information offered by the patient.
In addition, clinical examination and testing can be performed when applicable.
The patient's ability to function is critical in the evaluation.

While all patients should be screened routinely for OUD (and other substance use disorders), it is essential to perform this assessment before initiating opioid analgesics.
Continuously assessing for potential opioid misuse as well as monitoring for worsening or continued pain is recommended.
Referencing a Prescription Drug Monitoring Program (PDMP), an electronic database that relays information on filled prescriptions for controlled substances, can assist in identifying opioid misuse in an individual patient.

If opioid misuse is suspected or confirmed, referral for treatment should be offered.
A tool that can be used to help guide a practitioner on whether or not an opioid may be safely prescribed is the Opioid Risk Tool.
When a patient is on buprenorphine or methadone for treatment of OUD, doses should be confirmed before starting any new medications.

Goals of drug therapy
Buprenorphine and buprenorphine/naloxone
Methadone
Nonopioid and multimodal analgesia
Opioids

Why is methadone effective in treating OUD?
A. Has a very short half-life.
B. Increases euphoric effects of opioid agonists.
C. Reduces cravings.
D. More likely to produce tolerance.

C. Reduces cravings.
Rationale: Methadone is effective in treating OUD due to its very long half-life, which reduces cravings and dulls the euphoric effects of other opioid agonists. Because of its full mu opioid agonist properties, methadone is also efficacious in pain control and is thought to be less likely to produce tolerance due to its antagonistic effects at the N-methyl-d-aspartate (NMDA) receptor.

Reducing or eliminating pain and treating underlying injury/disease
Reducing or eliminating cravings
Preventing relapse
Minimizing or managing side effects
Improving quality of life

Which medication is not routinely used in the management of chronic pain?
A. Buprenorphine
B. Methadone
C. Naltrexone
D. None of the above

C. Naltrexone
Rationale: Medications used in OUD include buprenorphine, methadone, and naltrexone. Naltrexone, an opioid antagonist, is not routinely used in the management of chronic pain.

Continue buprenorphine once-daily maintenance and titrate a short-acting opioid to effect.
Divide total daily dose of buprenorphine and administer every 6 to 8 hours.
For anticipated acute pain from scheduled surgery, buprenorphine can be discontinued, or dosage can be reduced while full-opioid agonists are initiated (including methadone) for the treatment of anticipated postoperative pain.
When acute pain is resolved and opioids discontinued, the buprenorphine can be restarted after the patient is in confirmed withdrawal.

Pediatrics
Geriatric
Women
Nonpharmacologic

Self-reported pain and utilization of "as-needed" medications for treatment should be reassessed at all subsequent visits.
Discuss and manage any side effects that the patient may be experiencing. Patient's quality of life should also be considered.

Patients must be educated on proper administration of their pain medication.
Common side effects should be discussed with patients and follow-up appointments established. Encourage patients to report increased or recurring pain at their follow-up appointments.
Patients can also be educated on drug take-back program.

Identify the various components of cannabis.
Describe how the endocannabinoid system modulates pain.
Describe the relationship between tetrahydrocannabinol (THC) and cannabidiol (CBD) and the endocannabinoid system.
Identify potential drug-drug interactions and side effects of THC and CBD.

Cannabis as a plant
Cannabis as medicine
Cannabis's legal status

What type of pain are cannabinoids safe to use with minimal side effects?
A. Acute pain
B. Chronic pain
C. Rheumatoid arthritis
D. Fibromyalgia

B. Chronic pain
Rationale: Cannabinoids have been studied in the treatment of chronic pain in patients with neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Current evidence suggests that cannabinoids are safe with minimal side effects and are effective in reducing neuropathic pain specifically in fibromyalgia and rheumatoid arthritis.

Prior to 2018, marijuana and hemp were often considered the same, as they both are under the cannabis umbrella.
In 2018, Congress passed the Agricultural Improvement Act, also known as the 2018 Farm Bill, which separated, legally, marijuana and hemp.

Refresher on pathophysiology of pain
Endocannabinoid system and its relationship to pain
CB1 and CB2 receptors

Disease states where cannabis may be effective.
Cannabis and cannabinoid derivatives are becoming more accepted to treat a disease or alleviate symptoms.
However, the data supporting their efficacy for specific indications is not well established.

One of the key mantras used when treating patients with cannabis products is "start low, go slow." Depending on the product and the dose, the adverse effects of too high a dose may deter the user from adhering to treatment.

The goals of drug therapy using these agents is the same as any other agent used to treat pain.
With chronic pain, the goals of therapy are to decrease the pain to a tolerable level and improve function using a combination of various types of therapies to ultimately enhance quality of life.

Indicated for the treatment of anorexia associated with weight loss in acquired immunodeficiency syndrome (AIDS) patients and for the treatment of chemotherapy-induced nausea and vomiting.
Most common adverse reactions (>=3%) are abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, thinking abnormal, and vomiting.

Treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
Similar to dronabinol, nabilone also has psychotomimetic reactions, which are not normally observed with other antiemetic agents.
Early in treatment, euphoria and hypotension may occur, as well as impaired cognition. Delayed adverse reactions include depression, ataxia, and orthostatic hypotension. Less severe adverse reactions include drowsiness, headache, vertigo/dizziness, insomnia and/or fatigue, asthenia, and dry mouth.

Cannabidiol (CBD; Epidiolex(R)) is a 98% pure plant-derived oral CBD solution with a Food and Drug Administration (FDA)-approved indication for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) or Dravet Syndrome (DS) in pediatric patients 2 years of age and older.
It is the first plant-derived cannabis product approved by the FDA and is considered a nonpsychoactive cannabinoid.

Which medication has been approved by the FDA for the treatment of seizures associated with LGS in pediatric patients 2 years of age or older?
A. CBD
B. Nabilone
C. Dronabinol
D. Sativex

A. CBD
Rationale: CBD solution with an FDA-approved indication for the treatment of seizures associated with LGS. Dronabinol (Marinol; Syndros) is a synthetic tetrahydrocannabinol (THC) product which is indicated for the treatment of anorexia associated with weight loss in AIDS patients and for the treatment of chemotherapy-induced nausea and vomiting. Nabilone (Cesamet) is a synthetic derivative of THC, approved by the FDA for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Sativex is indicated for the "symptom improvement in adult patients with moderate-to-severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication" (Sativex Prescribing Info).

Combination treatment of THC and CBD (Sativex [Nabiximols] )
Terpenes and other chemicals enhancing pain
Selecting the most appropriate drug

Pediatrics
Geriatric
Women
Ethnic
Genomics
Monitoring patient response

Drug information
Patient-oriented information source
Nutrition/lifestyle changes