Pain Management in Chronic Pain

AUTHOR: AnnGene Anthony, MD, MPH, FAAFP

Definition

Chronic pain is pain that persists for longer than the expected time frame (typically >3 mo) or that is associated with progressive, nonmalignant disease. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. The perception of pain is influenced by physiologic, psychologic, and social factors. Chronic pain may be the direct result of an underlying disease process, or it may be a separate condition in its own right.

Synonyms

Chronic pain management

Nonmalignant chronic pain

Pain management

ICD-10CM CODES
G89.21		Chronic pain due to trauma
G89.22		Chronic post-thoracotomy pain
G89.3		Neoplasm-related pain (acute) (chronic)
G89.4		Chronic pain syndrome
G89.28		Other chronic post-procedural pain
G89.29		Other chronic pain

Epidemiology & Demographics

Estimates of the prevalence of chronic pain in the U.S. vary widely. A 2011 report from the Institute of Medicine, Relieving Pain in America, estimates that 116 million adults live with chronic pain at a cost of almost $635 billion per year. Chronic pain is the third-leading cause of physical impairment in the U.S. and the leading cause of disease burden and disability globally. Patients with chronic pain may also experience mood changes, depression, sleep disturbances, fatigue, and decreased overall physical functioning.

Clinical Presentation

History: Comprehensive patient assessment, including history of present illness (cause of pain, location, timing, characteristics, exacerbating/relieving factors, triggers), past therapies (pharmacologic and nonpharmacologic and outcomes of these therapies), medical history, family and social history, psychiatric history (including history of depression, anxiety, abuse, and/or other psychologic disorders), substance use history, allergies, sleep patterns and disturbances, and current medications. Social supports, coping mechanisms, and spirituality can also help guide development of a treatment plan.
Pain assessment should be performed at each visit; includes pain intensity (1 to 10), response to medication, and attributes of pain. Standardized templates for both initial and follow-up pain assessment have been developed by various organizations. The Brief Pain Inventory is an example of a widely used assessment tool. In addition, a functional assessment should be performed. Tools such as the Functional Ability Questionnaire (FAQ5) can guide the clinician in determining a patient’s functional status. Lastly, consider assessment of a patient’s risk for substance abuse. Table E1 summarizes questions to ask when pain persists.
Physical examination: Directed at systems affected by pain (often musculoskeletal) and neurologic examination.
Look for contributing factors (e.g., comorbidities, lifestyle factors) and barriers to effective care (e.g., behavioral, social, insurance). Increasing evidence points to a relation between obesity and chronic pain.
Components of a comprehensive assessment of cancer pain are summarized in Box E1.

TABLE E1 Questions to Ask When Pain Persists

Pain Syndromes: What is the Problem?	Selected Diagnostic Considerations	Consider:
Is there an ongoing physical disease? (e.g., infection, cancer)	MRI for anatomic pathology Gallium scan for infection ESR for infection, cancer PSA, CEA, p24 testing Pelvic, breast, prostate, gastrointestinal examination	Progression of disease Metastatic disease Visceral pain: Adhesions, referred pain, central pain
Is there a problem with the use and response to opioids? (e.g., misuse, lack of efficacy)	Central pain Opioids masking a psychiatric problem Opioid dosing error or inconsistency Opioid toxicity	Intravenous agents Antidepressants, anxiolytics, or sleep medications Opioid potency P450 2D6 codeine or oxycodone/SSRI interaction Meperidine toxicity
Is there a psychiatric disorder associated with pain? Depression Anxiety Somatic symptom disorder Psychosis Does CNS pain exist? (e.g., neuropathic pain)	Loss of all pleasure and mid-late insomnia Panic depersonalization, benzodiazepine failure, anxiety not relieved by analgesics Hypochondriasis Increased sensory threshold, decreased pain threshold Non-dermatomal distribution of pain Hyperpathia Allodynia, often opioid-resistant	Depression often masked by opioids or anxiolytics Co-morbid somatoform, mood, or anxiety disorders Pain drawing and explanation helpful for diagnosis Sharp sensation perceived as light touch is common Light touch is painful and sustained and has a delayed crescendo Tuning fork/moving a hair examinations detect allodynia best
Is it a pain behavior syndrome?	Somatic symptom disorder; rule out depression, substance use disorder, physical/sexual abuse, missed physical disorder	Anger and anxiety: Denied Counter-dependent, demanding style Passive and endearing
Is the patient faking? Malingering Factitious disorder	Malingering for drugs/disability Factitious deception to maintain the sick role	Malingering or factitious disorders with physical symptoms are rare, much more likely to be something else
Is an unusual problem responsible for pain?	Muscle trigger points absent, deep sleep	Myofascial pain often comorbid with other pain syndrome
Myofascial pain Porphyria Gastrointestinal pain Pelvic-visceral pain Neuropathic pain Sexual pain disorder	Laxative abuse, anorexia/bulimia Adhesions Hypoesthesia, allodynia Wasting illness, subcortical deficits/AIDS Conversion symptom, especially pelvic, gastrointestinal head pain	Visceral pain is diffuse, non-dermatomal, with sympathetic symptoms and may mimic psychiatric presentations Physical/sexual abuse antidote pain

ESR, Erythrocyte sedimentation rate; MRI, magnetic resonance imaging; SSRI, selective serotonin reuptake inhibitor.

From Stern TA: Massachusetts General Hospital Handbook of General Hospital Psychiatry, ed 7, Philadelphia, 2018, Elsevier.

BOX E1 Components of a Comprehensive Assessment of Cancer Pain

Detailed history of current pain problem
1. Catalog of pain (number and locations)
2. Information for each type of pain
  1. Intensity (0-10)
  2. Locations and radiation
  3. Onset and changes over time
  4. Temporal pattern (e.g., constant or intermittent) and quality (e.g., burning)
  5. Exacerbating and relieving factors
  6. Associated neurologic or vasomotor abnormalities
  7. Other associated factors
  8. Interference with the patient’s life
  9. Current therapeutic modalities (e.g., schedule, efficacy, and adverse effects)
  10. Prior therapeutic modalities (e.g., schedule, efficacy, and adverse effects)
Oncologic history
1. Histologic type
2. Presentation: Date, stage, and sites of involvement
3. Antineoplastic therapies: Dates, types, doses, toxicities, and response to each therapy
4. Current sites of disease: Stable, responding, or progressive
5. Patient expectations and goals
Medical history-may be affected by pain therapies
1. Coexisting diseases
2. Medications and allergies
3. Substance abuse history
4. Other constitutional symptoms such as anorexia, fatigue, sedation and other changes in mental status, nausea, vomiting, dysphagia, dyspnea, constipation, urinary and sexual dysfunction, depression, dry mouth; also, the ability to take medications by mouth and the presence of a central venous catheter
Personal and social history
1. Background: Age, education, employment, marital status, place of residence, religious affiliation, and cultural and ethnic background
2. Current status: Functional status, caregivers and their health and availability, support system
Physical examination
Review of additional information
1. Medical records, radiologic and laboratory studies
2. Family members, physicians and/or nurses who know the patient and his or her illness
Differential diagnosis
Recommendations regarding workup and therapy
Reassessment

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Etiology

The nervous system pathophysiology of chronic pain is described in Table E2. Mechanisms of chronic pain can be divided into three broad categories:

Nociceptive: Pain arising from damage to peripheral tissue from injury or inflammatory, mechanical, metabolic causes and alterations in cellular function
Neuropathic: Peripheral nerve impairment, newer research focusing on neurogenic inflammation
Central: Central disturbance in pain processing

TABLE E2 Chronic Pain: Nervous System Pathophysiology

Neurologic Mechanisms	Physiologic Effects	Clinical Implications
Neuroplasticity	Recruitment of cortical and subcortical neurons so wide dynamic range cells can be activated by low-threshold mechanoreceptors Allodynia Allesthesia	Early, concurrent, multi-modal treatment of nociceptive, central, vascular, sympathetic, and psychiatric aspects of the pain Block glutamate, substance P Early use of antiepileptic drugs, membrane stabilizers, sympatholytics NMDA antagonists
NMDA excess and glutamate-GABA imbalance Glutamate up, GABA down	Opioid tolerance Central hyperalgesia Hyperexcitability of peripheral and central pain cells	Normally nonpainful light touch, muscle and joint movements are painful Treatment options: Benzodiazepines, baclofen, antiepileptic drugs, substance P antagonists, or other NMDA antagonists (e.g., ketamine), GABA agents
Neurotoxins	Excitotoxic (e.g., quinolinic acid) Neuropathy	AIDS pain: Antiepileptic drugs, serotoninergic/noradrenergic agents, free radical scavengers
Opioid “off” mechanisms Off cells in the medulla Morphine 3G/morphine up Side effect intolerance	Hyperalgesia as opioids increase (particularly intrathecal) Tolerance as morphine 3G increases Side effects greater than benefit	Maintain steady blood levels of opioids, or decreased opioids may increase pain Switching to a different opioid if one does not work Trial off opioids if minimal response
Sympathetic pain	Mechano-allodynia, swelling Dystrophic changes	Sympathetic blockade and/or α-blocking drugs may be useful in CRPS, trauma, facial pain, arthritis
Monoamines (5-HT, NE, dopamine)	5-HT increase lessens opioid analgesia 5-HT1 dysregulation leads to vascular pain 5-HT1 involved in affective disorders/suffering of pain	Full dosage, early use of antidepressant drugs, including tricyclics, SSRIs, and dopamine agonists, alone or in combination NE re-uptake inhibitors (e.g., desipramine, venlafaxine) useful for pain whether depressed or not Pergolide and methylphenidate are useful adjuvants
Psychiatric illness	Decreased sleep Decreased muscle relaxation Alienation, anxiety	Differential diagnosis of psychiatric conditions and appropriate treatments

5-HT, 5-Hydroxytryptamine; CRPS, complex regional pain syndrome; GABA, γ-aminobutyric acid; NE, norepinephrine; NMDA, N-methyl-D-aspartate; SSRIs, selective serotonin re-uptake inhibitors.

From Stern TA: Massachusetts General Hospital Handbook of General Hospital Psychiatry, ed 7, Philadelphia, 2018, Elsevier.

Differential Diagnosis

Depends on etiology:
1. Nociceptive: Osteoarthritis, rheumatoid arthritis, postsurgical pain, posttraumatic, cancer pain
2. Neuropathic: Postherpetic neuralgia, diabetic neuropathy, nerve root compression
3. Central: Fibromyalgia, irritable bowel syndrome, chronic headache, phantom limb
Many chronic pain syndromes may involve one or more of the previously named mechanisms. The etiology of pain in cancer patients is summarized in Box E2.
Depression and anxiety disorders can be both a cause and a result of chronic pain, so temporal association of these disorders is important.
Coping mechanisms also can contribute to the risk of developing chronic pain. For example, anxiety and fear about pain is associated with an increased likelihood of developing chronic pain. Patients with a passive attitude toward treating pain (e.g., rest, medication use) also are associated with higher rates of chronic pain than those with active attitudes.
Genetic factors play a role. There are at least 150 genes that contribute to chronic pain. It has been shown to be a heritable phenotype, although no one set of genes has been identified as the culprit.
Factors such as socioeconomic background, employment status, physical activity, sleep disorders, and weight can have a bidirectional effect on chronic pain.

BOX E2 Etiology of Pain in Patients With Cancer

Direct tumor involvement (70%)
1. Invasion of bone
2. Invasion or compression of neural structures
3. Obstruction of hollow viscus or ductal system of solid viscus
4. Vascular obstruction or invasion
5. Mucous membrane ulceration or involvement
Cancer-induced syndromes (<10%)
1. Paraneoplastic syndromes
2. Pain associated with debility (e.g., bedsores, constipation, rectal or bladder spasms)
3. Other (e.g., postherpetic neuralgia)
Diagnostic or therapeutic procedures (20%)
1. Procedure-related pain (e.g., bone marrow aspiration or biopsy and lumbar puncture)
2. Acute postoperative pain or postsurgical syndromes (e.g., postmastectomy, postthoracotomy, and postamputation syndromes)
3. After radiation (e.g., injury to plexus or spinal cord, mucositis, and enteritis)
4. After chemotherapy (e.g., mucositis, peripheral neuropathy, and aseptic necrosis)
Pain unrelated to the malignancy or its treatment (<10%)

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Workup

Workup should be directed at identifying the source of pain. Identification of the mechanism of pain will guide the development of an appropriate treatment plan. Salient points in pain management and treatment are described in Table E3.
Laboratory testing, imaging studies, and/or electromyographic (EMG) studies should be used when etiology of chronic pain is unknown or unclear, when comorbidities are suspected, and as the history and physical examination direct.
Consider use of random urine drug screens or other tests to screen for presence of illegal drugs, unreported prescribed medications, or alcohol use.

TABLE E3 Pain Management and Treatment

Pain Characteristics	What Treatment is Next?	Comments
Nociceptive element present?	Nerve block for diagnostic and therapeutic reasons Imaging: MRI, looking for lesion	Even in pain that appears central (e.g., trigeminal neuralgia), nociceptive triggers can initiate pain and peripheral deafferentation
Allodynia present? (vibration, cold, or light touch)	Low-dose clonazepam (1-4 mg/day) if the person can tolerate benzodiazepines alone or in combination with desipramine 50 mg at bedtime (up to 300 mg eventually, if necessary) Mexiletine 150-400 mg TID	Allodynia predicts response to clonazepam Clonazepam relaxes muscles, improves sleep and anxiety Membrane stabilizers useful but cardiotoxicity needs to be checked Peptides useful
Paroxysmal attacks? (lightning-like)	Anti-epileptic drugs (AEDs) Carbamazepine 400-1600 mg/day (serum 8-12 g/L) Valproate 500-2000 mg/day Gabapentin 300-1200 mg TID Lamotrigine 100-300 mg/day	Clonazepam should usually be tried first, but works well synergistically with the AEDs listed Valproate for vascular headache Gabapentin: Few drug interactions
Central pain- Allodynia Paroxysmal attacks Sharp perceived as light touch Decreased pain threshold Nondermatomal distribution of pain Hyperpathia	Definitive trial is a single-blind random assignment of IV lorazepam (2-4 mg) vs lidocaine (100 mg) vs. morphine 10 mg, rated on a VAS pain Amitriptyline 25 mg IV infusion as test dose with VAS pain	Careful physical examination essential Is sharp perceived as light touch? Light touch is painful, sustained, and has a delayed crescendo Tuning fork/moving a hair examination best for allodynia
Comorbid central pain? Vascular and myofascial pain	Valproate 250-2000 mg/day Physical therapy Monoaminergic prescription antidepressants Nasal calcitonin 200 IU/day Capsaicin 4- to 6-wk trial Topical preparation	Common in head, neck, and face pain Mixed results with SSRIs Rule out sympathetically maintained pain
Psychiatric component? Rule out or treat	Comorbid psychiatric and CNS pain: Consider prescription with dual efficacy for pain and psychiatric diagnosis Benzodiazepine for allodynia and anxiety Antidepressants for neuropathy, depression, and anxiety Neuroleptics for neuralgia, anxiety, psychosis, and nausea AEDs for lancinating pain and mood stabilization	Rule out depression and anxiety, consider mimics of central pain, such as somatoform, factitious, or psychotic disorders Pain drawing by the patient is a good tool to uncover psychosis and myofascial pain Rule out akathisia, restless leg syndrome

AEDs, Anti-epileptic drugs; IV, intravenous; MRI, magnetic resonance imaging; SSRIs, selective serotonin reuptake inhibitors; VAS, visual analog scale.

From Stern TA: Massachusetts General Hospital Handbook of General Hospital Psychiatry, ed 7, Philadelphia, 2018, Elsevier.

Studies increasingly support the application of a multidisciplinary, biopsychosocial approach that addresses the multiple facets of pain and includes the patient’s perspective and goals.
Therapeutic goal is the reduction of pain (elimination of chronic pain is generally unlikely, and providers establish expectations and treatment goals from the outset).
A written care plan that includes methods to address the patient’s personal goals, improve sleep, increase physical activity, manage stress, and reduce pain. Increasing evidence re-enforces the role of patient education, self-management, and active coping skills in reducing pain perception and self-efficacy.

Nonpharmacologic Therapy

Exercise (recommended for all patients and tailored to individual abilities and needs). Recent studies demonstrate the benefit of tai chi for patients with osteoarthritis and yoga and therapeutic exercise for those with all forms of chronic pain. Low-impact exercise is encouraged for patients with chronic musculoskeletal pain
Modalities: Heat therapy, cold therapy, transcutaneous electrical nerve stimulation (TENS) units, manipulative therapy, cognitive behavioral therapy, psychologic counseling, and physical therapy
Electrostimulation therapy: TENS units (mixed evidence)
Behavioral therapies: Cognitive behavioral therapy (CBT), hypnosis, biofeedback, relaxation therapy, meditation, mindfulness trials have shown that primary care-based CBT produces modest but sustained reduction in measures of pain and pain-related disability compared with usual care, but do not reduce use or opioid medications
Music therapy (in conjunction with other types of therapy)
Virtual reality programs (through distraction and dissociation techniques therapy[ies]), biofeedback
Surgery (rarely considered a first-line therapy for chronic pain)
Commonly used interventional pain management techniques and indications are summarized in Table E4

TABLE E4 Commonly Used Interventional Pain Management Techniques and Indications

Name of Procedure		Indication
Celiac plexus block		Pancreatic cancer, chronic pancreatitis
Diskography		Diagnosis of anatomic localization of discogenic pain
Epidural corticosteroid injection		Lumbar, cervical, or thoracic radiculopathy
Facet joint block/medial branch block		Lumbar, cervical, or thoracic facet joint syndrome
Facet joint rhizotomy/radiofrequency lesioning		Lumbar or cervical facet joint syndrome
Gasserian ganglion block Maxillary nerve block		Trigeminal neuralgia
Greater occipital nerve block Lesser occipital nerve block Superficial cervical plexus block		Occipital neuralgia
Intravenous regional block		CRPS
Lumbar sympathetic block		CRPS of the legs
Percutaneous disk decompression		Lumbar or cervical disk herniation
Sacroiliac joint injection		Sacroiliac joint pain
Sphenopalatine ganglion block		Headache and facial pain
Spinal cord stimulator		CRPS, PVD, low back pain, angina
Stellate ganglion block		CRPS of arm, neck, and head; headache
Suprascapular nerve block		Shoulder pain
Vertebroplasty		Vertebral fracture
Motor cortex stimulation		Neuropathic pain
Deep brain stimulation		Neuropathic pain

CRPS, Complex regional pain syndrome; PVD, peripheral vascular disease.

From Jankovic J et al: Bradley and Daroff’s neurology in clinical practice, ed 8, Philadelphia 2022, Elsevier.

General Pharmacologic Rx

Short-acting antiinflammatory and analgesic medications (e.g., acetaminophen/NSAIDs/opioids). Avoid use of NSAIDs in patients with hypertension, congestive heart failure (CHF), or any type of chronic kidney disease (CKD). These medications should be considered first-line therapy for all patients without contraindications. Information on commonly used NSAIDs is summarized in Table E5.
Topical analgesics (lidocaine, NSAIDs, capsaicin) (Table E6).
Trigger-point or joint injections (immediate anesthetic plus long-acting corticosteroids).
Epidural steroid injections.
Nerve blocks (Table E7).
Analgesic adjuvants commonly used in chronic pain management are summarized in Table E8.
Antidepressants (tricyclic and selective serotonin reuptake inhibitors): Meta-analyses have shown reductions in pain and opiate use with administration of SNRIs in postoperative patients.
Anticonvulsant medications (e.g., carbamazepine, valproic acid, gabapentin, pregabalin); maybe helpful for neuropathic conditions.
Ketamine (N-methyl-D-aspartate [NMDA] receptor antagonist): Recent studies have been done on its use in patients with opioid tolerance and hyperalgesia. The efficacy of ketamine is moderate to weak, and it only should be considered as third-line treatment. Ketamine also requires regular infusion, and its efficacy is limited by side effects (mainly psychologic).
Implantable methods, epidural and intrathecal drug delivery systems, dorsal column stimulators.
Treatment of insomnia and sleep disorders to reduce pain with standard sleep-inducing agents (trazodone, antihistamines).
Many patients may require combination drug therapy (CDT) for adequate control of pain, with appropriate attention given to interactions and side effects. Commonly used adjuvant analgesics for cancer pain are summarized in Table E9.

Table E5 Information on Commonly Used Nonsteroidal Antiinflammatory Drugs

Drug	Route	Aging Effect	Precautions and Recommendations	Cost
Aspirin	PO, PR	GFR decreases, which results in decreased excretion	Evaluate risks and benefits Mostly used for cardiovascular protection	Generic
Ibuprofen	PO	Severity of GI toxicity increases with age and frequency	Treat acute or chronic inflammatory pain	Generic
Salsalate	PO	GI toxicity	GI toxicity lower than ASA	Generic
Naproxen	PO	COX-2 inhibitor, less GI toxicity; increases bleeding time	Moderate to severe inflammatory pain Low risk of cardiovascular events	Generic
Diclofenac	PO		Because of COX-2, selectivity has increased cardiovascular risk	Generic
Indomethacin	PO	More GI and central nervous system side effects	Not first-line drug for mild to moderate pain	Generic
Ketorolac	IM, PO	High GI toxicity and renal toxicity	Not recommended for long-term use	Generic
Nabumetone	PO	GI toxicity	Long half-life, low antiplatelet activity	750 mg 60 tabs $68.99
Celecoxib	PO	Selective COX-2 inhibitor	Fewer GI side effects	Generic

ASA, Acetylsalicylic acid (aspirin); COX-2, cyclooxygenase 2; GFR, glomerular filtration rate; GI, gastrointestinal; IM, intramuscular; PO, by mouth; PR, per rectum.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

Table E6 Topical Agents

Name	Route	Aging Effect	Precaution	Comparison	Cost
Acetaminophen	Oral	Transient elevation of alanine aminotransferase	In hepatic insufficiency and alcohol abuse patient	No effects of GI bleeding, adverse renal effects, cardiac toxicity as of NSAIDs Greater safety than NSAIDs so recommended as first-line therapy NSAIDs better for short-term pain-OA, low back pain Acetaminophen less effective for chronic inflammatory pain than NSAIDs	OTC, 100 tablets for $17.99
Lidocaine 5% patch	Topical	Nontoxic with safe range of 4 patches in 24 h	Skin irritation	Limited for neuropathic pain Absence of toxicity, no drug interactions. Contraindicated in advanced liver disease	Rx, $220.99 for a 30-patch box
Topical capsaicin cream	Topical		Burning sensation of skin	Some benefit in reduction of neuropathic and nonneuropathic pain	OTC
Topical NSAIDs	Topical	Reported toxicity is low when used in recommended doses. Not fully understood	Check renal and hepatic function periodically	Effective and safe over short term (<4 wk) Shown some efficacy in few studies of persistent pain management	Rx, 30 patches of 1.3% for $189.99

GI, Gastrointestinal; IM, intramuscular; NSAIDs, nonsteroidal antiinflammatory drugs; OA, osteoarthritis; OTC, over the counter.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

TABLE E7 Regional Anesthetic Techniques

	Types of Blocks	Examples	Indications	Comments
Local anesthetic blocks	Diagnostic	Intercostal nerve block	Determine etiology of pain and the response and adverse effects following local therapies	Analgesic effect will last only hours
	Treatment of sympathetically maintained pain	Stellate ganglion block	Sympathetically maintained pain	Repeated blocks might be needed
	Trigger point injections	Trigger point injection	Myofascial pain syndrome	Repeated blocks might be needed
Neurolytic (alcohol or phenol) blocks	Peripheral	Intercostal nerve blocks	Chest wall tumor	Pain relief usually lasts several months
Neurolytic (alcohol or phenol) blocks	Visceral	Celiac plexus block Superior hypogastric block Ganglionic impar block	Pancreatic cancer Gastrointestinal or genitourinary cancers	Pain relief usually lasts several months
	Neuraxial	Epidural	Pain localized to two or three dermatomes	Pain relief usually lasts several months
		Intrathecal neurolysis Spinal cord stimulator

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE E8 Analgesic Adjuvants

Agent	Dosage	Indications	Special Issues
Prostaglandin Inhibitors	Variable, limited by side effects and medical co-morbidity	Metastatic bone pain Inflammation Vascular pain	NSAID risks: Gastrointestinal bleeding, renal impairment
Dopamine Antagonists Phenothiazines Butyrophenones	Antipsychotic D₂ receptor blocking doses	Post-herpetic pain Cancer pain Diabetic neuropathy Adjunct to TCAs Co-morbid anxiety or delirium	Haloperidol binds to opioid receptors Membrane stabilizing
Stimulants			Stimulants decrease pain and sedation
Methylphenidate Dextroamphetamine Pergolide	5-50 mg/day (: 2-7 h) 5-20 mg/day (: 4-21 h) 0.05 mg TID (: 6-72 h)	Postoperative pain and pain in pediatric and cancer patients respond well to analgesic stimulant combinations	Appetite and cognition improve; methylphenidate shows better long-term efficacy than does amphetamine
Steroids
Prednisone	15+ mg/day PO	Bone metastases	Risks: Mood lability, withdrawal, anxiety, insomnia, gastrointestinal upset
Methylprednisolone	15 mg/kg IV boluses	Brain swelling
		Spinal cord compression
		Anorexia and pain
		Sickle cell pain
Peptides
Calcitonin	100-200 IU SC BID nasal 200 IC/day	Paget disease, metastatic, and myeloma pain	Intrathecal, nasal, and SC are used
Somatostatin	500 μg	Vascular headaches	Somatostatin inhibits SP
Capsaicin crème	0.075%	Neuralgia, cancer pain Hyperalgesia, postherpetic neuralgia, cluster headache, CRPS, inflammatory dermatoses, itching secondary to dialysis, psoriasis	Capsaicin effect peaks 4-6 wk, for diabetic, postmastectomy and arthritic pain
Antihistamines
Diphenhydramine	150 mg	Opioid adjunct	Decreased inflammation, 5-HT, NE, dopamine, SR spasm, opiate clearance increased opiate binding
Hydroxyzine	100 mg
Benzodiazepines
Clonazepam	1-4 mg/day	Adjuvant tricyclics	Not a substitute for diagnosis of depression or substance abuse
Lorazepam	2-16 mg/day	Allodynia
Antiepileptics
Phenytoin	300-450 mg/day	Cancer pain	Paroxysmal pain responds best to antiepileptic drugs
Carbamazepine	400-1600 mg/day	Headaches, neuralgia
Valproate	500-2000 mg/day	Central pain
Gabapentin	900-1800 mg/day	Neuropathy
Lamotrigine	100-300 mg/day	Migraine headaches
Oxcarbazepine	300-1600 mg/day	Neuropathy
Pregabalin	600-1200 mg/day	Neuropathy; PHN
Topiramate	200-400 mg/day	Neuropathy
Tricyclics	25-300 mg/day	Neuropathy	Burning
Desipramine Imipramine		Postherpetic neuralgia	Deafferentation pains respond best to the tricyclic drugs Increased side effects with amitriptyline
SSRIs		Diabetic neuropathy
Paroxetine	20-60 mg/day
Citalopram	20-60 mg/day
SNRIs		Diabetic neuropathy
Duloxetine	60-120 mg/day	Diabetic neuropathy; fibromyalgia
Venlafaxine	75-375 mg/day	Fibromyalgia

5-HT, 5-hydroxytryptamine; CRPS, complex regional pain syndrome; IV, intravenous; NE, norepinephrine; NSAID, nonsteroidal antiinflammatory drug; PHN, postherpetic neuralgia; SC, subcutaneous; SP, substance P; TCAs, tricyclic antidepressants.

From Stern TA: Massachusetts General Hospital Handbook of General Hospital Psychiatry, ed 7, Philadelphia, 2018, Elsevier.

TABLE E9 Commonly Used Adjuvant Analgesics for Cancer Pain

Drug Category	Indications	Drugs	Common Toxicities	Comments
Antidepressants	Neuropathic pain	Amitriptyline Nortriptyline Desipramine Duloxetine Venlafaxine	Sedation, dry mouth, constipation, postural hypotension, urinary retention	Begin with low doses and increase the dose every few days
Anticonvulsants	Neuropathic pain	Carbamazepine Pregabalin Clonazepam Gabapentin	Drowsiness, dizziness, nausea, rash, bone marrow depression	Monitor platelets with carbamazepine
Corticosteroids	Spinal cord compression, increased intracranial pressure, visceral distention	Dexamethasone Methylprednisolone Prednisone	Gastritis, insomnia, fluid retention, hyperglycemia, myopathy, increased appetite
Muscle relaxants	Muscle spasm	Diazepam Baclofen Methocarbamol Cyclobenzaprine	Sedation, dizziness, nausea, weakness, confusion
Benzodiazepines	Muscle spasm, myoclonus, anxiety, insomnia	Diazepam Lorazepam Alprazolam Midazolam Temazepam	Sedation, delirium, hypotension, headache, respiratory depression	Not analgesics; synergistic effect with opioids can cause respiratory depression
Antispasmodics	Gastrointestinal or bladder spasm	Diphenoxylate and atropine Loperamide Scopolamine patch Dicyclomine	Sedation, dry mouth, constipation
Neuroleptics	Delirium, agitation, nausea and vomiting, hiccups	Olanzapine Risperidone Quetiapine Haloperidol Prochlorperazine	Sedation, orthostatic hypotension, confusion, extrapyramidal reactions	Useful for symptoms other than pain
Bisphosphonates	Bone pain	Pamidronate Zoledronic acid Alendronate Risedronate Ibandronate Etidronate Denosumab	Hypocalcemia, fever, gastrointestinal disturbances, anemia	Delays time to painful skeletal events; also used with analgesics for bone pain

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Opioid Therapy

Although a mainstay of treatment over the past two decades, limited evidence is available demonstrating the efficacy of both immediate- and long-acting opioid preparations. Some patients with severe chronic pain syndromes may still benefit from this form of treatment. Full opioid agonists are generally the drug of choice for severe chronic cancer pain. Tenets of opioid prescribing are summarized in Box E3.
Opioids are rarely beneficial in the treatment of inflammatory or mechanical pain and are not indicated for treatment of headaches. Recent studies also have demonstrated the development of hyperalgesia with long-term opioid use.
The Centers for Disease Control and Prevention has published detailed guidelines for prescribing opioids for chronic pain in light of rising rates of opioid addiction and overdose. The guidelines include when and with whom to use opioid therapy, opioid selection, dosing, duration, and follow-up, along with assessment of the risks, benefits, and discontinuation of therapy.¹
Current recommendations include aiming for daily opioid doses of <50 morphine milligram equivalents (MMEs)/day to limit the risk of overdose and side effects, prescribing naloxone to patients receiving daily doses >50 MMEs/day due to risk of overdose, avoiding concomitant use with benzodiazepines, and avoiding doses >90 MMEs/day, or referral to a pain management specialist for close monitoring.
Sustained-release opioids (used for moderate to severe pain that has failed other therapeutic interventions): Oxycodone, morphine sustained release (SR), methadone (use with caution), or fentanyl patch; short-acting opioids can be used in conjunction with these agents for management of breakthrough pain. Conversion to a long-acting opioid should be based on an equianalgesic conversion. Table E10 compares MME doses for commonly prescribed opioids.

Table E11 describes common opioids used for cancer pain management. Titration of these medications should not exceed the equivalent of 100 mg morphine/day to avoid risk of overdose. Box E4 summarizes CDC recommendations for prescribing opioids for chronic pain outside of active cancer and palliative and end-of-life care. Box E5 summarizes the interpretation of recommendation categories and evidence types.

TABLE E10 Morphine Milligram Equivalent (MME) Doses for Commonly Prescribed Opioids

Opioid		Conversion Factor ∗
Codeine		0.15
Fentanyl transdermal (in μg/h)		2.4
Hydrocodone		1
Hydromorphone		4
Methadone
1-20 mg/day		4
21-40 mg/day		8
41-60 mg/day		10
≥61-80 mg/day		12
Morphine		1
Oxycodone		1.5
Oxymorphone		3
Tapentadol		0.4

Adapted from Von Korff M et al: De facto long-term opioid therapy for noncancer pain, Clin J Pain 24:521-527, 2008; Washington State Interagency Guideline on Prescribing Opioids for Pain, www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf.

From Dowell D et al: CDC guideline for prescribing opioids for chronic pain-United States, 2016, JAMA 315(15):1624-1645, 2016.

^∗Multiply the dose for each opioid by the conversion factor to determine the dose in MME.

TABLE E11 Common Opioids Used for Cancer Pain Management ^a

Agent	Parenteral (IM, SC, IV) (mg)	Oral (mg)	Duration (h)	Half-life (h)	Comments
Morphine	10	30	3-6 (PO) 8-24 (SR) 3-4 (P) 4-5 (R)	2-4	Many formulations for individual patient needs Controlled-release formulations available with variable durations Caution with CrCl <30 ml/min because of accumulation of metabolite
Hydromorphone	1.5	7.5	3-4 (PO/P/R)	2-3	Good choice for subcutaneous administration because of potency Controlled-release formulation available
Fentanyl	0.1	-	2-4 (TM) 0.5-4 (P) 48-72 (TD)	3-4	TD fentanyl 25 μg/h approximately equals 45 mg/day morphine (PO); TD has a slow onset and offset (12-24 h); optimal dosing of TM products is found through titration and not through ATC dose of opioid Metabolized via CYP3A4
Oxycodone	-	20	3-4 (PO) 12 (SR) 4-6 (R)	2-3	No ceiling dose if given without nonopioid analgesics Metabolized to active metabolite, oxymorphone via CYP2D6 Multiple controlled-release formulations with various durations and additional agents (e.g., naloxone, acetaminophen)
Oxymorphone	1	10	4-6 (PO)	9-11	ER formulation with and without abuse deterrent technology available Food increases AUC; take on empty stomach
Levorphanol	-	2	4-8 (PO)	12-16	Inconsistent supply in recent years Accumulates with repeated administration, especially days 2-5
Methadone	5	10	6-8 (PO/P)	15-150	Despite a long half-life, duration of analgesia is not prolonged; however, drug accumulation can result in toxicities; caution is warranted when converting to methadone in patients with high opioid tolerance Metabolized via CYP3A4 and CYP2B6 Monitor Q-Tc
Hydrocodone	-	30	4-6	4	Available as fixed combination with acetaminophen or aspirin and single-agent controlled-release formulation
Codeine	100	200	3-4 (PO/P)	2-4	10% of the population lack the enzyme needed to metabolize codeine to its active metabolite morphine Metabolized via CYP2D6 Polymorphisms may increase toxicity
Tramadol	100	120			Prodrug Metabolized via CYP2D6; profound effect in rapid metabolizers Serotonin reuptake inhibition Controlled-release formulation available Maximum doses 400 mg/day IR; 300 mg/day ER Caution in patients with seizures Risk of serotonin syndrome
Tapentadol	-	100			Noradrenergic reuptake inhibition Controlled-release formulation available Maximum doses 700 mg day 1, then 600 mg/day IR; 500 mg/day ER Metabolized via CYP2D6, CYP2C19, CYP2C9 Caution with SSRIs Equianalgesic dosage not well studied
Partial agonist: Buprenorphine	0.4	-		26-37	Partial mu agonist, weak kappa antagonist Available as once-weekly patch, single agent, and in combination with naloxone formulations Metabolized via CYP3A4, UGT1A3 May precipitate withdrawal in patients receiving full mu agonists

ATC, Around the clock; AUC, area under the curve; CrCl, creatinine clearance; ER, extended release; IM, intramuscular; IR, immediate release; IV, intravenous; P, parenteral; PO, oral; R, rectal; SC, subcutaneous; SR, sustained release; SSRIs, selective serotonin reuptake inhibitors; TD, transdermal; TM, transmucosal.

^aRefer to American Pain Society: Principles of analgesic use, ed 7 for opioid conversions.

BOX E3 Management Approach: Tenets of Opioid Prescribing

Order opioids on a scheduled “around-the-clock” basis to optimize relief. However for acute pain, opioids should be taken as needed rather than around the clock.
Order an as-needed opioid to treat breakthrough or incidental pain.
Initiate a prophylactic bowel regimen at the same time opioids are prescribed. Patients usually require a combination of stool softeners and stimulant laxatives to treat opioid-induced constipation.
Treat opioid-induced nausea and vomiting with aggressive antiemetic management, which includes giving patients antiemetics on an around-the-clock basis. Patients often become tolerant to this adverse effect several days after beginning opioids.
Once baseline opioid requirements are determined, sustained-release opioid preparations can be used to reduce the number of pills taken each day.
Teach the patient and family about the purpose and benefits of opioids to allay their fears about adverse effects and addiction. This instruction will improve patient compliance.
Frequent assessment of pain relief is paramount during the opioid titration period. Titrate doses based on the patient’s report of pain relief and/or the amount of as-needed opioid that has been required for patient comfort.
Maximize the doses of one opioid before changing to another agent or route. Changes should be made primarily because of toxicities. For example, a patient taking 200 mg of controlled-release morphine every 12 h and 200 mg of immediate-release morphine daily for breakthrough pain should have the dose of controlled-release morphine increased to 300 mg every 12 h if he or she is not experiencing significant opioid adverse effects. This approach is more likely to be beneficial than beginning titration with subcutaneous or intravenous morphine or oral hydromorphone.
Refer to equianalgesic tables when initiating or changing a patient’s analgesic regimen.
Avoid chronic administration of intramuscular or rectal opioids.
Avoid chronic administration of meperidine, which can be associated with the accumulation of normeperidine, a neurotoxic metabolite.
Urine drug testing is recommended before starting treatment and at least annually thereafter to assess for use of other controlled prescription drugs and/or illicit drugs.
Caution is recommended when opioids are prescribed concurrently with other CNS depressants, especially benzodiazepines.

Modified from Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

BOX E4 CDC Recommendations for Prescribing Opioids for Chronic Pain Outside Active Cancer, Palliative, and End-of-Life Care ^a

Determining When to Initiate or Continue Opioids for Chronic Pain

Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate.
Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic expectations for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety.
Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and the patient’s and clinician’s responsibilities for managing therapy.

Opioid Selection, Dosage, Duration, Follow-up, and Discontinuation

When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids.
When opioids are started, clinicians should prescribe the lowest effective dose. Clinicians should use caution when prescribing opioids at any level. They should reassess carefully the evidence of individual benefits and risks when increasing the dose to ≥50 morphine milligram equivalents (MMEs)/day, and they should avoid increasing it to ≥90 MMEs/day or should carefully justify a decision to titrate it to ≥90 MMEs/day.
Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or fewer often is sufficient; more than 7 days will rarely be needed.
Clinicians should evaluate risks and benefits in patients within 1 to 4 wk of starting opioid therapy for chronic pain or 1 to 4 wk of dose escalation. Clinicians should discuss risks and benefits of continued therapy with patients every 3 mo, or more frequently. If benefits do not outweigh risks of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or discontinue them.

Assessing Risk and Addressing Harms of Opioid Use

Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including offering naloxone when factors that increase risk for opioid overdose are present. These include history of overdose, history of substance use disorder, higher opioid dosages (≥50 MMEs/day), and concurrent benzodiazepine use.
Clinicians should review the patient’s history of controlled substance prescriptions and use state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, at time intervals ranging from every prescription refill to every 3 mo.
When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider retesting at least annually to assess for prescribed medications, other controlled prescription drugs, and illicit drugs.
Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.
Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder.

From Dowell D et al: CDC guideline for prescribing opioids for chronic pain-United States, 2016, JAMA 315(15):1624-1645, 2016.

BOX E5 Interpretation of Recommendation Categories and Evidence Types

Recommendation Categories

Based on evidence type, balance between desirable and undesirable effects, values and preferences, and resource allocation (cost)

Category A recommendation: Applies to all persons; most patients should receive the recommended course of action

Category B recommendation: Individual decision-making needed; different choices will be appropriate for different patients. Clinicians help patients arrive at a decision consistent with patient values and preferences and specific clinical situations

Evidence Type

Based on study design and a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and constellation of plausible biases that could change effects

Type 1 evidence: Randomized clinical trials or overwhelming evidence from observational studies
Type 2 evidence: Randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies
Type 3 evidence: Observational studies or randomized clinical trials with notable limitations
Type 4 evidence: Clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations

From Dowell D et al: CDC guideline for prescribing opioids for chronic pain-United States, 2016, JAMA 315(15):1624-1645, 2016.

Medical Marijuana

Cannabis-based products: Oral, synthetic cannabis products with high THC-to-CBD ratios and sublingual, extracted cannabis products with comparable THC-to-CBD ratios may be associated with short-term improvements in chronic pain and increased risk for dizziness and sedation. Studies are needed on long-term outcomes and further evaluation of product formulation effects.²
Preclinical studies demonstrate potential benefits of cannabinoids, with a good safety profile; however, the evidence for use in the clinical setting is limited because of nonclinical factors.
Some small, randomized controlled trials (RCTs) show benefit of low-dose cannabinoids for chronic neuropathic pain.
Newer RCTs note a positive impact of cannabidiol (CBD) on reduction of opiate medication use and improvement of quality-of-life indicators.

Complementary & Alternative Medicine

Acupuncture and massage (evidence-based for some indications). Acupuncture is most likely to benefit patients with low back pain, neck pain, chronic idiopathic or tension headache, migraine, and knee osteoarthritis. Auricular-point acupressure has shown promise for several chronic pain syndromes and can be self-administered. Recent evidence has demonstrated the benefit of modalities such as yoga, tai chi, and music therapies. Supplements, although popular, do not have substantial evidence to recommend for or against their use.

Referral

Pain medicine specialist or multidisciplinary pain clinic: Useful when primary therapies fail, in patients with complex pain conditions, in patients requiring a high daily MME, or for invasive therapies
Consider referral to an addiction specialist if patient has a history of substance abuse or addiction
Psychiatry/psychologic services for counseling, if needed

a All recommendations are category A (i.e., apply to all patients outside active cancer treatment, palliative care, and end-of-life care) except recommendation 10 (designated category B, with individual decision-making required).

Patient consent should be obtained in the form of a written treatment agreement before initiating treatment. This agreement should outline the goals of therapy, use of a single provider or treatment team and a single pharmacy, limitations on dose and number of prescribed medications, prohibition on use with alcohol or sedating medications, keeping medication safe and secure, prohibition on selling or sharing medication, limitations on refills, compliance with all components of the treatment plan, the role of drug screening, and consequences of nonadherence.
Follow-up assessment should occur every 1 to 6 mo and include a complete pain assessment (see earlier), review of the type of long-acting analgesic used and dosage, use of breakthrough analgesics, side effects and their management, use of nonpharmacologic therapies, and adjunct medication use.

Comments

Medication dependence and addiction should not be confused. Most patients receiving chronic opioid therapy can become dependent on these medications for pain relief without developing opioid addiction. Patients exhibiting signs of addiction often will seek escalating doses of medication, request refills of prescriptions earlier than planned, and engage in drug-seeking activities (e.g., emergency department visits between prescriptions, seeking multiple prescriptions).
Side effects need not preclude use of opioid medications and should be anticipated. Antiemetics can aid in controlling nausea. Constipation can be managed with stool softeners and laxatives.
The emphasis of comprehensive pain management for noncancer-related chronic pain has led to a fourfold increase in prescribing of opioid medications in the U.S. This increase in opiate use has also led to a rise in the misuse and abuse of these medications. Providers should proceed with caution before initiating pain management with opiate medications and should familiarize themselves with processes and tools for pain assessment and medication management. Forty-two states have developed prescription drug monitoring programs (PDMPs) to assist providers in identifying issues of abuse, polypharmacy, and misuse of controlled substances.
In 2022 the U.S. Department of Veterans Affairs (VA), the U.S. Department of Defense (DoD), and the CDC released updated opioid guidelines. Both guidelines recommend against use of opioids for the treatment of chronic pain, and both guidelines recommend against the use of extended-release opioids. Both guidelines recommend that when opioids are prescribed, clinicians prescribe the lowest dose possible for the shortest time based on an assessment of the patient. Both support ongoing evaluation of benefits and harms when opioids are used to manage pain .³

Patient & Family Education

National Pain Foundation (www.painconnection.org)
National Institutes of Health (www.nih.gov)

Related Content

Pain Medications (Patient Information)

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