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Nonnarcotic Methods of Pain Management: Review Article
Nonnarcotic Methods of Pain Management: Review Article
Review Article
P
From the Department of Clinical Medi- ain is “an unpleasant sensory and emotional experience associ-
cine, Danish Pain Research Center, Aarhus ated with actual or potential tissue damage, or [is] described in terms of
University, and the Department of Neurol-
ogy, Aarhus University Hospital — both in such damage” when there is no physical derangement.1 The function of pain
Aarhus, Denmark. Address reprint requests is to protect the body by making the organism aware of damaging events and to
to Dr. Finnerup at f innerup@clin.au.dk. promote healing by causing sensitivity to movement or other stimuli that may
N Engl J Med 2019;380:2440-8. delay recovery. However, pain is not always related to tissue damage and does not
DOI: 10.1056/NEJMra1807061 always serve a protective function. This is the case with neuropathic pain, which
Copyright © 2019 Massachusetts Medical Society.
is caused by a lesion or disease of the somatosensory parts of the nervous system,
and with some other chronic pain conditions, such as fibromyalgia and migraine.2
Acute and chronic pain may cause suffering and interfere with daily life, factors
that influence the choice of treatment.
Acute pain is the most common reason for visiting an emergency department,3
and surgical procedures are often associated with acute postoperative pain.4,5
Chronic pain also causes suffering, as reflected by the finding in the Global Burden
of Disease Study 2013 that chronic low back pain was the leading cause of years
lived with disability.6 In addition to the contribution of pain to disability, that
study showed that the associated problem of opioid use disorders accounted for
5.8 million additional years lived with disability,6 an observation that underpins
attempts to treat pain with drugs other than opioids. Long-term opioid adminis-
tration has minimal effects on chronic pain and can cause tolerance, drowsiness,
and dependence, as well as impaired memory, concentration, and judgment.7 For
these reasons, the International Association for the Study of Pain recommends
caution in prescribing opioids for chronic pain,8 and there has been an increased
emphasis on the use of nonopioid pain management.
The choice of treatment for pain depends on many factors, and the heterogene-
ity and large number of acute and chronic pain conditions preclude a general treat-
ment algorithm. In cooperation with the World Health Organization, the Interna-
tional Association for the Study of Pain has developed a classification of chronic
pain for the 11th revision of the International Classification of Diseases2 (Table 1), and
a similar classification has been proposed for acute pain,5 providing the bases for
facilitating treatment pathways.
A sse ssmen t of Pa in
A common way to assess pain is to ask the patient about the intensity of pain on
an 11-point numerical scale (0 to 10), but an overemphasis on the effect of treat-
ment on pain intensity and overdependence on the assessment of pain with the
use of these scales can lead to unnecessary opioid use.9 Furthermore, pain inten-
sity does not reflect the entirety of the pain experience and is often not a measure
of the suffering induced by pain.10 If the pain is known to be short-lived or to serve
a purpose such as healing, it may be accepted and tolerated by the patient. Also,
evidence is of only low-to-moderate quality.16-18 Aspirin (acetylsalicylic acid) and other NSAIDs,
Multidisciplinary management of chronic pain, unlike acetaminophen, have antiinflammatory
which addresses psychological, social, and oc- properties and inhibit platelet aggregation. Side
cupational factors, is sometimes beneficial, but effects of NSAIDs include nausea, gastrointesti-
no specific components of the combined treat- nal bleeding, and hypersensitivity reactions.
ment approach have been identified that influ- NSAIDs, with the exception of aspirin, are as-
ence the success of treatment.19,20 Hypnosis as a sociated with a risk, albeit low, of heart attack or
treatment for pain has been studied in a few stroke. The magnitude of the risk is not known
randomized trials, with either uncertain evidence with certainty, suggesting that the lowest doses
of an effect or small effect sizes on self-reported should be used for the shortest time possible.24
chronic pain; variable effect sizes on emotional NSAIDs are used for slight-to-moderate pain such
stress resulting from pain during medical inter- as muscle and joint pain, toothache, menstrual
ventions have been noted.21 pain, certain types of visceral pain, and postop-
The lack of high-quality evidence supporting erative pain and are first-line treatment for con-
the long-term effects of self-management and ditions such as migraine and single episodes of
psychological treatment,16 in combination with tension-type headache.25
patients or physicians who may not follow the
recommended approaches, results in wide varia- Antidepressant Agents
tions in practice.12 Barriers to implementation of Several drugs initially developed for the treat-
these approaches include resistance on the part ment of depression have been used for chronic
of the patient, lack of resources, limitations of pain. Tricyclic antidepressants and serotonin–
insurance coverage, and uncoordinated health norepinephrine (noradrenaline) reuptake inhibi-
care systems. Further studies are needed to de- tors (SNRIs) reduce the intensity of pain in pa-
termine when and how these strategies should tients who have depression and in those who do
be implemented.12 not.26 One randomized, controlled trial estimated
that less than 12% of the effect of duloxetine at
a dose of 60 mg or 120 mg was attributable to
Nonopioid A na l ge sic Agen t s
improvement in mood or anxiety.27 However,
Several analgesic agents, developed primarily for antidepressants may be more effective in pa-
conditions other than pain and with various bio- tients with both pain and depressive symptoms
logic sites of action, are available (Fig. 1 and than in those with pain alone.28 The reason for
Table 2). These include nonsteroidal antiinflam- the analgesic effect is not known but may be
matory drugs (NSAIDs), antidepressant agents, related in part to presynaptic inhibition of the
and antiepileptic drugs. reuptake of serotonin and norepinephrine in pain
inhibitory pathways, as well as peripheral mech-
Acetaminophen, Aspirin, and NSAIDs anisms involving β2-adrenergic receptors and the
Acetaminophen (also known as paracetamol) has opioid system.29,30
well-known analgesic and antipyretic effects. It Tricyclic antidepressants and SNRIs have been
is widely used as an over-the-counter and pre- used as first-line treatments for neuropathic
scription analgesic, but its mechanisms of action pain, defined as pain due to a lesion or disease
are not known. There is a small risk of severe of the peripheral or central somatosensory ner-
skin reactions and a risk of liver damage if this vous system.31 In a systematic review of trials
agent is used in large doses. Acetaminophen has of these agents as compared with placebo, the
been the leading cause of acute liver failure in number of patients who would need to be treat-
the United States since 1998 and requires a ed (number needed to treat) in order to achieve
warning about the hepatotoxic risks.22 Although at least a 50% reduction in neuropathic pain in
acetaminophen is still considered the safest one patient was 3.6 for tricyclic antidepressants
analgesic, no high-quality studies have assessed and 6.4 for SNRIs.31 Antidepressants have also
chronic adverse effects, and the Food and Drug been recommended for prophylactic treatment
Administration (FDA) is monitoring the safety of of migraine and tension-type headache.32 There
its use during pregnancy.23 is some evidence of an analgesic effect of these
Serotonin and
Alpha-A norepinephrine
Cortex
5-HT reuptake
Ascending α2-Adrenergic receptor agonists
pathway Tricyclic antidepressants
Neuromodulation
Descending SNRI
inhibitory
pathway
Dorsal-root
ganglion
Nav
Alpha-A BTX-A
5-HT
Brain
NMDAR Gabapentin
stem Tricyclic antidepressants
Nav Ca2+
Ketamine Pregabalin
Carbamazepine
Oxcarbazepine Primary afferent
Lacosamide nerve
Lamotrigine
Bupivacaine
Lidocaine
Sensory-nerve
endings
Primary afferent
nerve
Spinal cord
2444
Drug Dose† Indication Side Effects and Risks‡ Other Information
Acetaminophen 650 mg orally every 4 to 6 hr; maxi- Mild-to-moderate pain Overdose can cause liver damage No evidence of an effect on neuropathic
mum dose, 4000 mg/day; also pain
available as injection
Aspirin 350–650 mg orally every 4 hr; maxi- Mild pain (temporary use), Nausea, dyspepsia, abdominal pain, bleed- Contraindicated in patients with known
mum dose, 3600 mg/day; individ- inflammatory rheumatic ing tendency, tinnitus, headache, dizzi- hypersensitivity; should not be used
ual doses for rheumatic diseases diseases ness, insomnia, hypersensitivity reac- in children under 16 yr of age (risk of
tions; risk of gastrointestinal bleeding Reye’s syndrome); no evidence of an
effect on neuropathic pain
NSAIDs Dose depends on the specific drug Mild-to-moderate pain, pain Nausea, dyspepsia, diarrhea, constipation, Contraindicated in patients with known
associated with inflam headache, dizziness, somnolence, hyper- hypersensitivity; recommended dose is
mation sensitivity reactions; risks of gastrointes- the lowest effective dose for the shortest
tinal bleeding, myocardial infarction, period; no evidence of an effect on neu-
stroke ropathic pain
Amitriptyline§ 25–150 mg orally once daily or in two Neuropathic pain (first-line Somnolence, tremor, dizziness, headache, Patients with poor metabolism of CYP2D6
divided doses;¶ maximum single therapy), fibromyalgia, drowsiness, tachycardia, orthostatic require lower doses; abrupt discontinua-
The
dose, 75 mg; daily doses above prevention of tension-type hypotension, dry mouth, constipation, tion should be avoided; contraindicated
75 mg/day should be used with headache or migraine nausea, micturition disorder, weight in patients with recent myocardial in-
caution in patients >65 yr of age gain, hyperhidrosis, decreased libido; farction or cardiac rhythm disorders;
increased risk of suicidal thoughts caution required if used with other
serotonergic agents
Duloxetine 60–120 mg orally once daily or in Neuropathic pain (first-line Nausea, headache, dry mouth, somnolence, Abrupt discontinuation should be avoided;
two divided doses¶ therapy), chronic musculo- dizziness, increased blood pressure; caution required if used with other sero-
skeletal pain, fibromyalgia increased risk of suicidal thoughts tonergic agents
Gabapentin 900–3600 mg/day orally in three First-line therapy for neuro Dizziness, somnolence, peripheral edema, Dose adjustment required in patients with
divided doses¶ pathic pain fever, infection, nausea, lack of coordi compromised renal function; misuse,
nation, blurred vision; increased risk of abuse, and dependence have been
suicidal thoughts reported
n e w e ng l a n d j o u r na l
Pregabalin 300–600 mg/day orally in two divided Neuropathic pain (first-line Dizziness, somnolence, headache, periph Dose adjustment required in patients with
doses¶ therapy), fibromyalgia eral edema, nausea, weight gain, dis compromised renal function; misuse,
orientation, blurred vision; increased abuse, and dependence have been
risk of suicidal thoughts reported
Capsaicin, 8% patch 1–4 Patches applied to intact skin Peripheral neuropathic pain Application-site pain and erythema, tran- Applied by a health care professional wear-
for 30 or 60 min every 3 mo sient increase in blood pressure; risk ing nitrile gloves
of reduced sensation
* The drugs listed are those commonly used, but the list does not include all analgesics used for all pain conditions. CYP2D6 denotes cytochrome P-450 2D6, EMA European Medicines
Downloaded from nejm.org on May 28, 2020. For personal use only. No other uses without permission.
Agency, FDA Food and Drug Administration, and NSAID nonsteroidal antiinflammatory drug.
† Doses are given for adults.
‡ For a comprehensive list of side effects, risks, contraindications, and warnings, refer to the product information for each drug.
§ Other tricyclic antidepressants (imipramine, desipramine, and nortriptyline) have not been evaluated as extensively for the treatment of pain but may be associated with more accept-
able side-effects profiles.
¶ The starting dose is lower.
Nonnarcotic Methods of Pain Management
given subcutaneously in the region of pain is active self-care, and meditation and yoga are rec-
a third-line treatment for peripheral neuropath- ommended to improve psychological well-being.41
ic pain.31 However, the quality of evidence supporting the
recommendations for complementary therapies
is low, and there is controversy about the clinical
In terv en t iona l Pa in
M a nagemen t relevance of the effects of these therapies, the
role of placebo responses, and trial design, par-
Surgery is indicated for the treatment of pain if ticularly in the case of acupuncture.43
the underlying cause can be addressed safely and
with a net clinical benefit. Examples that fulfill F u t ur e Dir ec t ions
these conditions include removal of a tumor or
herniated disk adjacent to neural tissue. Devices Pharmacologic and interventional treatments for
designed to modulate abnormal activity in the chronic pain often provide no reduction or only
nervous system by stimulating neuronal path- a small reduction in pain and are often judged
ways are used for symptomatic pain treatment. by the patient to be inadequate.34 Each approach
There is weak evidence for a benefit of spinal may have side effects that are associated with a
cord stimulation in patients with painful dia- decreased quality of life and interference with
betic polyneuropathy, postsurgical chronic back daily activities.44 Education and training of health
and leg pain, or complex regional pain syn- care professionals to ensure cost-effective and
drome, and the evidence is similarly weak for a safe evidence-based treatments are therefore
benefit of repetitive transcranial magnetic stim- considered essential for pain management.12,25
ulation in the treatment of neuropathic pain and Recent advances in our understanding of the
pain from fibromyalgia; in various other condi- mechanisms underlying pain have led to the de-
tions, the effect of these devices is absent or velopment of new approaches. Several drugs are
unclear.40 The effect of spinal cord stimulation under investigation, such as calcitonin gene–
has been compared with the effect of conven- related peptide antagonists and serotonin
tional care or reoperation for low back pain, and (5-hydroxytryptamine) type 1F (5-HT1F) agonists
most studies have been of short duration, mak- for migraine and angiotensin II type 2 receptor
ing it difficult to estimate effect sizes over the antagonists, selective sodium-channel blockers
long term.40 (e.g., voltage-gated sodium channel Nav1.7), and
Interventional treatments are available for pain vanilloid receptor antagonists for neuropathic
conditions such as microvascular decompression pain.45,46 New but not rigorously tested interven-
or percutaneous radiofrequency rhizotomy for tional treatments include high-frequency spinal
trigeminal neuralgia and occipital-nerve stimu- cord stimulation and dorsal-root ganglion stim-
lation for cluster headache. Epidural analgesia or ulation. Well-known drugs such as the anesthet-
intrathecal treatment with ziconotide (a selective ics ketamine (an N-methyl-d-aspartate [NMDA]
N-type voltage-gated calcium channel blocker), receptor antagonist) and nitrous oxide are also
clonidine (a central α2-adrenergic receptor ago- being considered as alternatives to opioids for
nist), bupivacaine, or a combination of these acute pain in the emergency department or as part
agents may be used for uncontrolled pain asso- of analgesic regimens for postoperative pain.45,47,48
ciated with cancer. Attempts are being made to identify biomark-
ers that predict the likelihood that a treatment
will be effective49 by targeting the pain mecha-
C ompl emen ta r y Ther a pie s
nism in each patient. For example, one study
Many patients with chronic pain use comple- showed that refined testing of somatosensory
mentary therapies, which include meditation, function in patients with neuropathic pain could
yoga, acupuncture, music therapy, heat therapy, identify patients who would have a response to
massage, chiropractic, guided imagery, and bio- the sodium-channel blocker oxcarbazepine.50
feedback.41,42 Complementary therapies such as Other possible methods that could individualize
acupuncture and massage are recommended by the approach to pain treatment include molecu-
the American College of Physicians for chronic lar profiling in rare pain conditions caused by
low back pain.15 These therapies may support gene variants that code for specific sodium
channels, brain imaging to assess brain net- opioid-related adverse effects and dependence.4,25,48
works involved in pain and its emotional effects, Patient education, psychological treatments, and
and assessment of psychological functioning that avoidance of opioids may be useful for the man-
may suggest a benefit from the use of specific agement of chronic pain.12
psychological treatments.49 Dr. Finnerup reports receiving fees for serving on a data and
safety monitoring board from Mitsubishi Tanabe, lecture fees
from Astellas, grant support and advisory board fees from No-
C onclusions vartis Pharma, advisory board fees from Teva Pharmaceuticals
and Merck Selbstmedikation, consulting fees and travel support
For the management of acute pain, the use of from Grünenthal, and grant support from Innovative Medicines
multiple approaches that do not include opioids Initiative. No other potential conflict of interest relevant to this
article was reported.
and the establishment of acute pain services for Disclosure forms provided by the author are available with the
postoperative pain management can reduce full text of this article at NEJM.org.
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