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Screening and risk stratification

Comperhensive evaluation establishing diagnosis

Confirm inadequacy of non-opioid and non-pharmacological treatmen

Complete thorough risk stratification assesment

Establish treatment goals and emphasize trial parameters

Ensure that the balance of risk and benefit favors treatment

Explain benefits, risks, trial and monitoring policies

Obtain written, signed pain management plan obtain urine toxicology specimen

Therapeutic trial (up to 8 weeks)

Start therapy at low standard dose and increase dose as tolerated to achieve acceptable

Individualize doses and titration scheme

Consider repeating urine toxicology testing

Discontinue opioid if trial targets not achieved

Continue treatment if trial targets are achieved without significant side effect

Stable phase Maintain stable dose

Require patient to pick prescriptions in person montly

Assess and document patients pain relief, functional ability, side effect, behaviors, urine result, quality of
life, prescription monitoring program reviews

Treat side effect\urine toxicology testing at least annually in low risk patients

Dose escalation

Excluede or identify disease Treatment failed

Treatment successful
progression. Criteria for failure: failureto
Pain relief that improves wellbeing,
Hospitalize, if necessary maintain trial goals, evidence of
progress toward goals, improved
addiction, abuse, misuse, diversion
quality of life
Repeat therapeutic trial phase and/or non-compliance
Continue stable dose
Aim to reach new stable dose Wean and discontinue therapy

Obtain urine toxicology specimen

Dose escalation failed

Consider opioid rotation:

Switch opioid and start at lower

dose or wean and discontinue

Restart opioid after period of

abstinence if necessary

Figure 16.1 opioid for chronic non-terminal pain treatment paradigm

Table 17.2 Number-needed-to-treat (NNT), values for topical analgesics in several pain

Topical agent Condition (number of NNT (95% Cl) Reference

NSAIDs Osteoarthritis, 4.6 (3.8-5.9) [2]
musculoskeletal pain,
rheumatism, back pain
(14) [2]
Soft tissue injury (26) 3.8 (3.4-4.4)
(strains, sprains).
Post-herpatic neuralgia 4.4 (2.5-17.5) [6]
Lidocain 5% patch (1)
Neuropathic pain 5.7 (4.0-10) [9]
Capsaicin 0.075% (6)
Musculoskeletal pain 8.1 (4.6-34) [9]
0.015% (3)
Acute pain (7) Evidence not robust [10]
Rubefacients Chronic pain (9) 6.2 (4.0-13) [10]
Tabel 17.3 Peripheral trgets being explored as potentiai novel tropical analgesics [16]

Target Comments
Na + channel Na, 1.7, Na,1.8 and Na,1.9 most promosing targets; much interest in isoform
specific blockers and tropicaals
K+ channels Various K+ channels subtypes implicated in analgesia by several drugs; no
specific topical exploration.
Ca2+ channels -conotoxin and gabapentin/pregabalin interact with Ca2+ channels, limited
topical exploration.
Adenosine receptors Peripheral A1 receptors inhibit pain: A1 receptor antagonists inhibit peripheral
analgesia by amitriptyline; topical actions of amitriptyline being explored.
Acid sensitive ion ASICs selectivel localizes on sensory nerves and involved in saveral forms of
chaannels pain; topical aspects not yet developed.
Vanillioid and TRP TRPV1 activated then desensitized by capsaicin; at least 13 TPRV1 receptor
receptors antagonists in preclinical development as analgesics; antagonists could
potentially be novel class of topical analgesics.
Glutamate receptors Ionotropic and metabotropic GluR antagonists being examined in preclinical
studis; ketamine given tropically in human neuropathic pain.
Serotonin receptors Peripheral 5-HT18 and 5-HT10 receptors inhibit pain; 5-HT2, 5-HT3, 5-HT4, and
5-HT7 receptor facilitate pain; analgesia occurs with ketanserin (5-HT2A
antagonist) applied topically in preclinical studies.
Adrenergic receptors 1-,2- and -Ars implicated in pain facilitation; Ars involved in sympathetic-
sensory coupling and interact with P2X3 receptors; nerve injry produces
complex effect on expression of AR subtypes; clinical studies have examined
topical clonidine; interest in topical P2X3 receptores antagonists.
Cholinergic AchRs involved in peripheral pain; M4 mAChRs feasible target for analgesia;
mechanisms nAChs also pesent on sensory afferent; nAChR agonist (epibatidine, ABT-
594), and antagonist (-conotoxin) explored as systemic analgesics; botulinum
toxin (blocks Ach release) explored as analgesic; topicals not extensively
Cannabinoids Peripheral CB1 and CB2 receptores involved in pain; mixed agonists given
sysemically for neuropathic pain; CB1 and CB2 agonists attractive targets for
tofical approaches.
Opioids Inflammtory pain reduced by peripherally acting morphine; effects in chronic
inflammation may also reflect anti-inflammatory actions on immune cells;
peripherally restrited, - and K-agonists are targets of interest; interest in
topical development (skin, mucosa)
CGRP, substance P Peptides present in sensory afferents involved in pain signaling in the spinal
cord and role in neurogenic inflamationin periphery; anatagonists explored as
systemic analgesic but NK 1 antagonists have not been successful clinically,
no topical development.
Somatostatin Analogs exhibit systemic and spinal analgesia; peripheral analgesia occurs
perhaps via opioid release from immune cells; intra-articular application of
somatostatinrelieves pain in rheumatoid arthrittis; no topical development
Cytokines Several cytokines involed in nociception; TNF ligands and IL-1 receptor
antagonist used for rheumatoid arthritis; prostaglandin receptor anagonists are
novel targets as topical analgesicst (cf. Topical NSAID efficacy)
Neurotrophic factors NGF is pronociceptive; increased NGF levels occur in several inflammatory
pain conditions, antagonism of NGF considered promising theuraphetic target;
no topical exploration.