Best Dx/Best Rx: Pain

Pain

Alan C. Carver, MD
Mount Sinai School of Medicine

Definition/Key Clinical Features
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

May be of physical or psychological origin
Acute pain is the most common symptom for which patients seek medical evaluation
Prevalence in cancer patients, ~ 14%–100%; prevalence in AIDS patients, ~ 30%–90%
Undertreatment is a significant clinical problem

Best Tests

Pain history
- Onset
- Temporality and presence of breakthrough pain
- Location
- Quality of pain
- Intensity: validated scales can help evaluation
  - Numeric Pain Intensity Scale
  - Visual Analog Scale
  - Faces Pain Scale for Adults and Children
- Aggravating/relieving factors
- Associated symptoms
Response to current and previous treatment approaches
Patient's psychological state
- Stress
- Clinical depression
- Anxiety
- Mental status
Impact of pain on quality of life, including social, psychological, and spiritual well-being
- Medical Outcomes Study 36-Item Short Form (SF-36)
- Sickness Impact Profile
Impact of pain on life functions
- Work, family, social responsibilities or relationships
- Activities of daily living
- Other important activities
- Eating and sleeping
- Brief Pain Inventory
Past medical history
- Acute and chronic conditions that may cause pain
- Substance abuse and/or dependence
Comprehensive physical examination
- Pain behaviors
  - Abnormal gait or posture
  - Guarding
- Signs of systemic illness
- Neurologic exam
Diagnostic tests appropriate to the pain-causing disease processes
Patient expectations and goals regarding pain intensity, daily function, quality of life

Best Therapy

Individualize therapeutic approach
Refer to pain specialist or multidisciplinary team when appropriate
Provide continuity of care throughout evaluation and treatment
Reassess patient's pain complaints and response to therapy
Choose the simplest approach before more complicated and invasive techniques
Involve patient in therapeutic choices
Titrate doses to maximize efficacy and minimize side effects
Anticipate and treat side effects
World Health Organization analgesic ladder: effective in 70%–100% of adult patients
- Step One: for mild pain
  - NSAIDs and acetaminophen
- Step Two: for mild to moderate pain
  - Weak opioids (e.g., codeine, hydrocodone)
  - Combination analgesics (e.g., oxycodone/acetaminophen) plus NSAID and adjuvants as needed
- Step Three: for severe pain
  - Potent opioids (e.g., morphine, methadone, hydromorphone, fentanyl) plus NSAID and adjuvants as needed
Use adjuvant medications at any level of the WHO ladder
- Corticosteroids (the most widely used adjuvants)
- Antidepressants, anticonvulsants, and other agents for neuropathic pain
- Bisphosphonates and radionuclides for bone pain
- Antibiotics for pain from ulcerating tumors
Nonpharmacologic adjuvant therapy
- External-beam radiation
- Neurosurgical ablative procedures
- Psychiatric therapy
- Anesthesia

Opioids

Indications
- Acute pain
- Trauma-related pain
- Postoperative pain
- Cancer pain
- Some chronic noncancer pain (e.g., osteoarthritis, low back pain, neuropathic pain)
Choice of agent
- Based on drug and patient characteristics
- Morphine plus gabapentin may be more effective for neuropathic pain than either agent alone
- Failure of response to an adequate trial of one opioid should be followed by an adequate trial of another opioid
Administration
- Oral or transdermal
  - For systemic treatment of chronic conditions if possible
- Intravenous
  - Rapid titration and onset of analgesia
  - Avoids first-pass hepatic degradation
  - Yields higher bioavailability and opportunity to reduce total dose
  - May provide consistent level of analgesia
  - Useful alternative for patients unable to take orally
  - Increased risk of systemic side effects
- Subcutaneous injection
  - When small fluid volumes sufficient to deliver prescribed dose
  - Rapid titration and onset of analgesia
  - Shortened duration of effect requires continuous infusion or frequent redosing to maintain constant pain relief
  - Risk of side effects is greater than with oral route
- Rectal
  - Absorption and first-pass metabolism varies
  - Cannot be used in patients with diarrhea, transmucosal lesions, neutropenia, or severe thrombocytopenia
- Transdermal
  - When oral route is unavailable
  - Limited by available skin surface
  - Not effective for fluctuating pain levels
- Intramuscular: avoid because of erratic absorption and associated pain
- Patient-controlled analgesia (PCA)
  - For initiation of parenteral opioid therapy, rapid opioid titration, or treatment of incident pain
  - Continuous infusion may be programmed to supplement PCA doses, enabling sleep and covering baseline pain
  - Equivalent or superior analgesia with the following advantages:
    - Less total opioid consumption
    - Fewer side effects
    - No greater likelihood of dependence
    - May be used in the home
- Intraspinal
  - For patients requiring large doses
  - Only for patients who have had pain relief but intolerable side effects with other regimens
  - Achieves analgesia at significantly smaller doses than with systemic administration
  - Intrathecal morphine is 100 times more potent than I.V.
Duration of action
- Long-acting and sustained release for patients in continuous pain, as in cancer
- Around-the-clock administration may improve outcomes and adherence
- Short-acting formulations to manage intermittent and breakthrough pain
Dosing
- Begin with immediate-release oral agent with a short half-life for 24–48 hr and monitor consumption, efficacy of pain relief, and side effects
  - Patients in severe pain may need rapid titration of a potent opioid via continuous I.V. infusion
- Long-acting or sustained-release forms may be prescribed once titration to optimal dose is achieved
- Change doses in increments of one third to one half the prior dose
- Reduce or eliminate dose gradually (in increments < 25% of daily dose) if patient becomes pain free
- Short-acting, immediate-release opioids to cover breakthrough pain for patients on long-acting therapy
  - Single rescue doses of 10%–20% of total daily dose or 25%–30% of single standing dose
  - Adjusted as appropriate for the individual
  - Where possible, use the same agent for standing and breakthrough medications
Conversion
- Inflammatory or neuropathic pain may be better treated with adjuvant analgesics than with modification of opioid therapy
- Pain of opioid side effects may only need treatment of the adverse effect
- Refractory pain or intolerable side effects may require conversion in these settings:
  - Pain is opioid responsive
  - Current drug was titrated to maximal effect
  - Side effects are already optimally managed
- Choice of opioids may be based on patient's past experience with opioids of a given class or receptor profile
- Equianalgesic conversion tables should be consulted to arrive at a starting point for dosing
- If patient is receiving multiple opioids, conversion should be based on total dose of all prior agents, expressed as morphine equivalents
- If conversion is prompted by intolerable side effects but pain control is adequate, the calculated dose should next be reduced by ~ 25%–50%
- If conversion is prompted by inadequate analgesia, the new agent may be started at or near an equianalgesic dose
- Provide additional short-acting opioids during titration of new drug for breakthrough pain
- Reassess pain and total daily dose for the first 2 wk after conversion, with titration of extended-release and breakthrough doses as appropriate
- Avoid inadequate pain control and excessive narcosis during conversion
Side effects
- Sedation
  - Occurs with onset of therapy or increase in dose; usually resolves within 3–7 days
  - Of concern in the elderly and those taking concurrent sedating medications
  - Eliminate nonessential sedating medications
  - Use stimulants (e.g., caffeine, methylphenidate) for cancer patients with significant persistent sedation
    - Use with caution in the elderly
    - Not recommended for patients with sedation due to opioid management of chronic pain
- Nausea
  - Frequently resolves shortly after treatment onset
  - Antiemetics during first 1–2 days of opioids may help
    - Ondansetron, 4 mg I.V.
    - Prochlorperazine, 5–10 mg t.i.d.–q.i.d.
    - Hydroxyzine
      
      May alleviate centrally induced nausea
      Dose: 25–100 mg t.i.d.–q.i.d.
    - Metoclopramide
      
      May reduce nausea caused by slowed gastric motility
      Dose: 10 mg q.i.d.; maximum daily dose, 500 µl/kg
    - Scopolamine
      
      May alleviate motion-exacerbated nausea in ambulatory patients
      Dose: transdermal, 1.5 mg postauricular patch q. 3 days
      May have significant anticholinergic side effects, particularly in the elderly
- Constipation
  - Does not improve with time
  - Often underdiagnosed
  - May lead to anorexia, vomiting, abdominal pain, obstruction, impaction, and perforation
  - Appropriate dietary changes
  - Assess for constipation in patients on around-the-clock opioids
  - Stool softeners and stimulant laxatives
- Respiratory depression
  - Rare side effect in opioid-naive patients receiving large doses and in head injury or pulmonary disease
  - Monitor sedation level and respiratory status during first 24 hr of therapy in opioid-naive patients
  - Stop opioids until depression resolves, then resume at 75% of previous dose
  - Spirometry and oxygen may be useful
  - Treat severe respiratory depression with I.V. naloxone
    - Dose: 2 mg I.V. in 500 ml normal saline or D5W
- Confusion
  - Occurs primarily in high-dose or prolonged opioid therapy and in decreased renal function
  - Patients with previous cognitive impairment at additional risk
  - Symptoms include delirium, agitation, myoclonus, hyperalgesia
  - Of particular concern in the elderly or those with concurrent CNS disease
  - Nonessential medications with CNS effects should not be prescribed for elderly patients requiring opioid therapy
  - Neuroleptics may be useful against confusion, mental clouding, or persistent delirium
- Pruritus
  - Diphenhydramine, 25–50 mg q. 4–6 hr
  - Hydroxyzine, 25–100 mg t.i.d.–q.i.d.
- Myoclonus
  - Clonazepam, 0.5 mg t.i.d.; increase by 0.5–1 mg q. 3 days to maximum of 20 mg/day
Tolerance
- A higher dose of agent is required to maintain a given effect
- There is no clinical limit to tolerance
- Rarely develops in stable disease
- Increasing requirements for previously controlled chronic pain should prompt comprehensive evaluation
Physical dependence
- A withdrawal syndrome could be produced by the following:
  - Abrupt cessation of drug administration
  - Rapid reduction in dose
  - Decreasing blood level of drug
  - Administration of an antagonist or mixed agonist-antagonist
- Universal with prolonged opioid therapy
- To avoid withdrawal, all patients receiving opioids for ≥ 1 wk should have drug tapered rather than abruptly discontinued
Psychological dependence (addiction)
- Differentiate from physical dependence
- Impaired control over drug use, compulsive use, continued use despite harm, and craving
- Extremely low prevalence in patients taking opioids for pain relief
- Pseudoaddiction
  - More common than true addiction
  - Patients with poorly managed pain mimic signs of psychological dependence
    - Drug seeking
    - Increased focus on obtaining medications
    - Possibly illicit drug use or deception
  - Behaviors resolve with effective pain management
  - May be exacerbated by curtailing of opioid therapy

NSAIDs and Acetaminophen

No tolerance or physical dependence
Indications
- Especially useful for muscle and joint, bone, dental, postoperative, and inflammatory pain
- May suffice for mild or moderate pain
- For severe pain, may be added to an opioid regimen for opioid-sparing effect and enhanced pain relief
Ceiling effect for analgesia
NSAID side effects
- GI symptoms
- GI bleeding
- Hypersensitivity
- Kidney dysfunction
- CNS effects
- Often dose dependent
NSAIDs may be used with GI-protective drugs
Use acetaminophen with caution in patients with liver disease

Corticosteroids

Indications
- Cancer pain
  - Pain of spinal cord compression
  - Increased intracranial pressure
  - Superior vena cava syndrome
  - Metastatic bone pain
  - Neuropathic pain secondary to infiltration or compression by tumor
  - Hepatic capsule distention
- High doses for inpatients with advanced disease in acute pain crisis
- Pain related to musculoskeletal conditions
Oral or injectable
Side effects
- Well tolerated for short-term treatment
- Toxicities
  - Often arise with prolonged high-dose therapy
  - Adrenocortical insufficiency
  - Hypertension
  - Immune suppression, masking of signs of infection
  - Glaucoma
  - Electrolyte imbalances
  - GI ulceration and/or bleeding
  - Osteoporosis and/or pathologic fracture
  - Psychiatric disturbance or psychosis
- Avoid withdrawal syndrome upon discontinuance

Antiepileptic Drugs

Indications
- Adjuvants for neuropathic pain
  - Peripheral diabetic neuropathy
  - Postherpetic neuralgia
  - Reflex sympathetic dystrophy
  - Trigeminal and glossopharyngeal neuralgia
  - HIV neuropathy
  - Spinal cord injury–related dysesthesias
- Postlaminectomy pain
- Phantom limb pain
- Cancer pain
Gabapentin: first-line treatment for neuropathic pain
- Well tolerated (except for cognitive effects in the elderly)
- Side effects: sedation, nausea/vomiting, dizziness
- Dose: 100 mg p.o., q. 8 hr (maximum, 3,600 mg/day in divided doses)
Carbamazepine
- First-line treatment for trigeminal neuralgia
- Second- or third-line agent for other neuropathic pain conditions
- Dose: 50–60 mg/day
- Monitor for hyponatremia and leukopenia
- Use only if gabapentin has failed or is not tolerated
- May cause thrombocytopenia or liver damage
Topiramate: adjuvant analgesic for neuropathic pain
- Dose: 100–200 mg/day
- Must be titrated slowly (no faster than 25 mg/wk) to decrease side effects such as cognitive slowing and paresthesias

Tricyclic Antidepressants (TCAs)

Indications
- Adjuvants for neuropathic pain
  - Painful diabetic neuropathy
  - Postherpetic neuralgia
  - Chronic facial pain
  - Central pain
- Adjuvants for chronic pain
  - Cancer pain
  - Chronic low back pain
  - Osteoarthritis
Efficacy: comparable to antiepileptics
Amitriptyline: alternate choice
- Strongest anticholinergic profile
- Given at bedtime
Nortriptyline: alternate choice
- Less anticholinergic effect
- Better choice for older patients
Imipramine: alternate choice
Dose for TCAs: 10–25 mg, to maximum of 150 mg/day, if tolerated
Side effects of TCAs: elderly are most susceptible
- Sedation
- Hypotension
- Constipation
- Urinary retention
- May cause lethal cardiac arrhythmias at very high doses (contraindicated in patients with conduction abnormalities)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Useful in managing neuropathic pain
Second-line choice for refractoriness or poor tolerability with other agents
Paroxetine
- Dose: 20–50 mg/day
Venlafaxine
- Dose: 37.5–225 mg/day

Topical Analgesics

5% lidocaine patch
- First choice for postherpetic neuralgia
- Wear patch for 12 consecutive hours over the area of pain, then discard; apply a new patch 12 hr later
EMLA (lidocaine 2.5% and prilocaine 2.5%)
- Effective in children for needle insertions, blood draws, etc.

Selective Cyclooxygenase-2 Inhibitor

Celecoxib
- Helpful for some patients, particularly those at low risk for coronary artery disease or cerebrovascular disease
- Dose: 100–200 mg b.i.d.

Best References

Portenoy RK, et al: Lancet 353:1695, 1999 [PMID 10335806]

SUPPORT Principal Investigators: JAMA 274:1591, 1995 [PMID 7474243]

Zech DF, et al: Pain 63:65, 1995 [PMID 8577492]

The author is a member of the speakers' bureaus of Pfizer/Pharmacia, GlaxoSmithKline, and Ortho-McNeil Pharmaceutical, Inc.

April 2006