Evidence and consensus recommendations for the pharmacological management of pain in India

Figures & data

Table 1 Different types of pain

Type	Pathophysiology	Characteristics	Examples
Based on underlying pathophysiology
Nociceptive pain	Activation of nociceptors in response to noxious stimuli	Sharp, burning pain (somatic) or dull, aching pain (visceral)	Back pain, headaches, neck pain, shoulder pain, pain due to burns and injuries
Neuropathic pain	Central sensitization or neuronal damage	Severe, burning, shooting or numbing pain, increased sensitivity to stimuli (hyperalgesia and allodynia)	Peripheral neuropathy, diabetic neuropathy, trigeminal neuralgia, complex regional pain syndrome (CRPS), neuropathic pain due to spinal injury
Mixed pain	Nociceptive and neuropathic origin	Severe, shooting pain or dull, aching pain or pain with mixed characteristics	LBP with radiculopathy, cancer pain
Based on duration
Acute pain	Activation of peripheral nociceptors, accompanied by release of COX enzymes and prostaglandins	Lasts from few seconds to less than 6 months	Injuries, headaches, sprains, postoperative pain, back pain
Chronic pain	Sensitization at the level of spinal neurons via multiple mechanisms	Lasts for ≥6 months	Chronic primary pain, cancer pain, posttraumatic and postsurgical pain, neuropathic pain, headache and orofacial pain, visceral pain, musculoskeletal pain
Breakthrough pain	Pain in a well-treated patient due to movement (incidental), spontaneous or resulting from weaning off of drugs or effect of drug	Lasts from few seconds to hours	Cancer pain
Based on etiology
Cancer pain	Caused due to cancer itself (brain tumors, breast cancer), drug treatment (chemotherapy, radiation) or associated disease (neuropathy)	Acute or chronic pain of mild, moderate or severe intensity with/without breakthrough pain	All types of cancers
CNCP	May have multiple etiologies	Moderate-to-severe pain with/without restricted mobility	Rheumatoid arthritis, osteoarthritis
Based on location
LBP	Caused due to bad posture, strains/sprains, underlying disease (malignancy or infection) or referred pain (kidney or gall stones)	Mild and moderate-to-severe pain with/without impaired movement or physical function	Acute LBP, herniated disk, spondylosis
Neck pain and shoulder pain	Caused due to strains, sprains, incorrect posture and compression of spinal cord or injuries	Mild and moderate-to-severe pain with/without impaired movement or physical function	Axial neck pain, cervical radiculopathy
Headaches	Caused due to incorrect posture, stress, migraine or underlying disease (tumors)	Headache associated with migraine may present additional symptoms (aura), visual problems or vertigo	Tension-type headaches, migraine headaches
Referred pain	Type of visceral pain that radiates to surrounding regions	May be sharp, pulsating pain or dull, aching pain depending upon the origin	Angina (jaws and shoulders), stones (abdomen and back)

Abbreviations: CNCP, chronic noncancer pain; COX, cyclooxygenase; LBP, low-back pain.

Figure 1 Mechanism of peripheral versus central sensitization.

Notes: (A) Peripheral sensitization and (B) central sensitization. Activation of peripheral nociceptors on the skin in response to stimuli, such as heat, injury or mechanical pressure, initiates the release of chemical mediators at the site of injury (peripheral sensitization). Persistent pain or inflammation causes activation and repetitive firing in afferent C-fiber nociceptors, which triggers the release of excitatory neurotransmitter glutamate in the synapse of the dorsal horn (central sensitization). This is accompanied by the release of substance P, BDNF and neurokinins, which causes persistent depolarization of the cell membrane. Additionally, activation of AMPA or NMDA receptors by glutamate stimulates the microglia and subsequently induces the release of cyclooxygenase enzymes 1 and 2, nitric oxide and other proinflammatory mediators (TNF-α, IL-1, IL-6).
Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; ASIC, acid-sensing ion channels; BDNF, brain-derived neurotropic factor; 5-HT, 5-hydroxytryptamine; IL, interleukin; NMDA, N-methyl-d-aspartate receptor; NGF, nerve growth factor; PG, prostaglandin; NK₁, neurokinin-1; TNF, tumor necrosis factor; TrkB, tyrosine receptor kinase B; TRPV, transient receptor potential vanilloid receptor.

Figure 2 Therapeutic modulation of the pain-processing pathway.

Abbreviations: NMDA, N-methyl-d-aspartate receptor; NSAID, nonsteroidal anti-inflammatory drug.

Table 2 Available therapies for treatment of pain

Class	Molecules	Indications	Dosage	Common adverse events
Aniline analgesics	Acetaminophen	Acute/chronic pain	500–1,000 mg every 4–6 h; max dose of 4,000 mg/d	Hepatotoxicity
NSAIDs-Salicylate	Aspirin	Acute/chronic pain	500–1,000 mg every 4–6 h; max dose of 4,000 mg/d	GI upset/irritation, hepatic and renal dysfunction, fluid retention, hypersensitivity reaction
NSAIDs-Aryl acetic acid derivative	Diclofenac	Acute/chronic pain	50–100 mg/d; max 150 mg/d	GI upset/irritation, nausea and vomiting, weakness, headache, dizziness, hepatic and renal dysfunction, hypersensitivity reaction
NSAIDs- Propionate	Ibuprofen	Acute pain	400–800 mg every 6–8 h; max dose of 3,200 mg/d	GI upset/irritation, hepatic and renal dysfunction, fluid retention, hypersensitivity reaction, cardiovascular events in high-risk patients
	Naproxen	Chronic pain	250–500 mg every 8–12 h; max dose of 1,500 mg/d	GI upset/irritation, hepatic and renal dysfunction, fluid retention, hypersensitivity reaction, cardiovascular events in high-risk patients
COX-2 inhibitor	Colecoxib	Acute/chronic pain	200–400 mg every 12–24 h; max dose of 400 mg/d	GI upset/irritation, hepatic and renal dysfunction, fluid retention, hypersensitivity reaction, cardiovascular events in high-risk patients
	Rofecoxib	Acute/chronic Pain	12.5–50 mg once a day	GI upset/irritation, hepatic and renal dysfunction, fluid retention, hypersensitivity reaction, cardiovascular events in high-risk patients
Opiate	Codeine	Chronic pain	30–60 mg every 4 h as needed	Constipation, nausea, vomiting, sedation and pruritus; less common effects include dry mouth, mental confusion, urinary retention and respiratory depression
	Hydrocodone	Chronic pain	5–10 mg every 4 h as needed	Constipation, nausea, vomiting, sedation and pruritus; less common effects include dry mouth, mental confusion, urinary retention and respiratory depression
	Oxycodone	Chronic pain	5–10 mg every 4 h as needed	Constipation, nausea, vomiting, sedation and pruritus; less common effects include dry mouth, mental confusion, urinary retention and respiratory depression
	Morphine	Chronic pain	5–30 mg every 4 h	Constipation, nausea, vomiting, sedation and pruritus; less common effects include dry mouth, mental confusion, urinary retention and respiratory depression
	Tramadol	Acute/chronic pain	5–100 mg every 4–6 h; max dose of 400 mg/d	Constipation, somnolence, dizziness, nausea, vomiting and pruritus
Antiepileptic	Gabapentin	Acute/chronic pain	300–900 mg thrice daily; max dose of 3,600 mg/d	Dizziness, somnolence and peripheral edema
	Pregabalin	Acute/chronic pain	50–300 mg/d	Dizziness, somnolence and peripheral edema
	Carbamazepine	Acute/chronic pain	200–600 mg twice daily	Somnolence, mental confusion, dizziness and nausea
	Oxcarbazepine	Acute/chronic pain	1,200–2,400 mg/d	Changes in vision, dizziness, confusion and depression
Tricyclic antidepressants	Amitriptyline, nortriptyline	Acute pain	10–150 mg/d (amitriptyline), 25–100 mg/d (nortriptyline)	Drowsiness, dry mouth, dizziness and constipation
SNRIs	Duloxetine, venlafaxine	Chronic pain	40–60 mg/d (duloxetine), 150 mg/d (venlafaxine)	Nausea, gastrointestinal bleeding and increase in hepatic enzymes

Notes: Data from American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons (2009),²⁹ Patel et al,³⁸ McPherson et al (2004),²³⁹ Bell and Schnitzer (2001),²⁴⁰ Antman et al (2007),²⁴¹ Dworkin et al (2010),²⁴² and Cleeland and Ryan.^243,244

Abbreviations: d, day; h, hour; max, maximum; COX, cyclooxygenase; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; SNRI, serotonin–norepinephrine reuptake inhibitor.

Table 3 Different pain assessment scales for measuring the intensity of pain

Assessment scale	Number of items	Components	Outcome	Applicability	Limitation
Unidimensional pain scales
VAS	1–10	Numerical scale (0: no pain; to 10: unbearable pain)	Pain intensity	Adults with acute or chronic pain	Cognitively affected adults, elderly and children
VRS	1–10	Verbal descriptor scale (0: no pain; to 10: worst imaginable pain)	Pain intensity	Adults with acute or chronic pain	Illiterate and cognitively affected
NRS	1–10	Numerical scale with markings (0: no pain; to 10: worst imaginable pain)	Pain intensity	Adults with chronic pain, elderly and illiterate population	–
Faces Pain Scale	1–10	Pictoral representation of faces expressing varying degrees of pain (0: no pain; to 10: worst pain)	Pain intensity	Children, elderly or cognitively impaired patients	Subjective differences in interpretation of scale may affect results
Multidimensional pain scales
BPI	4-item scale	4 grades for pain severity (0: no pain; to 10: pain as bad as you can imagine) and 7 grades for pain interference on a 7-item scale (0: does not interfere; to 10: completely interferes)	Pain intensity and functional status	Adults with chronic pain due to cancer, rheumatoid arthritis or peripheral neuropathy	–
MPQ	78 words	4 classes of descriptors with 78 items (20 groups of words) to describe the quality of pain	Subjective pain experience	Adults with neuropathic, arthritic and other types of chronic pain	Time consuming, difficult to administer to cognitively affected or illiterate patients
Disease-specific pain scales
Neuropathic pain scale	10 items	Verbal descriptors of pain (0: no pain; to 10: most sharp/dull/hot/intense/cold sensation imaginable)	Intensity, quality and mechanism of pain	Postherpetic neuralgia, diabetic neuropathy
LANSS Pain Scale	7 items	Interview and sensory examination (allodynia, altered pinprick threshold)	Intensity and mechanism of pain	Differentiation between neuropathic and nonneuropathic pain
RAPS	24 items	Pain severity and interference (0: never; to 6: always)	Pain intensity and functional status	Rheumatoid arthritis
Pain scales for elderly patients
Abbey’s Pain Scale	6 items	Nonverbal descriptors of pain severity (0: absent, 1: mild, 2: moderate, 3: severe)	Pain intensity, physical and behavioral changes	Elderly patients with dementia	Self-reporting of pain not possible
PADE	24 items	Behavioral descriptors	Physical, global (pain intensity) and functional status	Elderly patients with dementia	Inconsistent narrative descriptors, difficult to administer by caregivers

Abbreviations: BPI, Brief Pain Inventory; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs; MPQ, McGill Pain Questionnaire; NRS, Numerical Rating Scale; PADE, Pain Assessment for the Dementing Elderly; RAPS, Rheumatoid Arthritis Pain Scale; VRS, Verbal Rating Scale; VAS, Visual Analog Scale.

Figure 3 Pain algorithm.

Notes: ^aAvoid in age >60 years, cardiovascular/GI/renal comorbidities; ^bavoid long-term therapy in opioid dependence/tolerance; ^cfirst-line therapy for acute NP, NP due to cancer, acute exacerbations of severe NP as well as when titrating one of the first-line medications, if prompt relief of pain is required.
Abbreviations: GI, gastrointestinal; NP, neuropathic pain; NSAID, nonsteroidal anti-inflammatory drug; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Table S1 Treatment recommendations

Type of pain	First-line therapy	Second-line therapy
Diabetic neuropathy	Gabapentin, pregabalin, tricyclic antidepressants (amitriptyline, imipramine, desipramine) [A]	Opioids (oxycodone, tramadol) [A]
Postherpetic neuralgia	Gabapentin, pregabalin, nortriptyline, amitriptyline, topical capsaicin, topical lidocaine [A]	Tramadol, oxycodone [A]
Fibromyalgia	Amitriptyline, pregabalin [A]	Duloxetine [B]
Trigeminal neuralgia	Carbamazepine [A]	Baclofen, lamotrigine, gamma-knife surgery [B]
Low-back pain	NSAIDs (ibuprofen, diclofenac) [A], opioids (tramadol, codeine) [B]	Strong opioids (morphine, fentanyl) [A], antidepressants (amitriptyline, nortriptyline) [A], anticonvulsants (gabapentin, pregabalin) [C]
Neck pain	Physiotherapy, exercise, acetaminophen, NSAIDs [A]	Opioids, anticonvulsants, antidepressants, muscle relaxants, acupuncture, single-point injections [B, C]
Migraine headache	Sumatriptan, zolmitriptan [A], NSAIDs (ibuprofen) [A], antiemetics (prochlorperazine, chlorpromazine) [A]	Ergotamine, dihydroergotamine [B], opioids (morphine, tramadol) [B]
Tension-type or cluster headache	Acetaminophen, NSAIDs (ibuprofen, ketoprofen, diclofenac, naproxen) [A]	Acetaminophen–caffeine [A], NSAID–caffeine combination [A], relaxation and acupuncture [C]
Arthritic pain	Acetaminophen [A], NSAIDs [A], weak opioids (tramadol, codeine) [A]	Strong opioids (morphine, oxycodone) [B], antidepressants (amitriptyline, nortriptyline) [C]
Cancer pain	Weak opioids (codeine, tramadol) with/without NSAIDs [A]	Strong opioids (morphine, oxycodone, fentanyl) [A]

Note: Recommendations were graded by an expert panel based on available evidence. Grade A: based on evidence Level 1. Grade B: based on evidence Level 2 or extrapolated from Level 1. Grade C: based on evidence Level 3 or extrapolated from Level 1 and 2.

Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.

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