Pain

Behavioural

Analgesic requirements

Physiology

Self-reporting

Gate control theory of pain

Proposes that pain pathways (Aδ + C) are blocked by the stimulation of touch fibres (Aβ), which inhibit transmission to ascending pathways via an interneurone in the substantia gelatinosa (Fig. 10.2).

Figure 10.2 Gate control theory of pain.

Pre-emptive analgesia

Concept introduced by Crile in 1913. Delivering pre-emptive analgesia was thought to reduce postoperative problems such as phantom limb pain, but subsequent studies have not confirmed this.

Combination analgesia

Combinations of opioids, NSAIDs and nerve blocks result in improved pain relief and fewer adverse side-effects. Most effective to use a combination strategy using multimodal drugs of increasing potency (Fig. 10.3).

Figure 10.3 Pain ladder of escalating therapy (World Health Organisation).

Interruption at specific sites

Reduced peripheral stimulus (e.g. NSAIDs), interrupted peripheral pain transmission (e.g. local anaesthetic), interrupted central pain transmission (e.g. anterolateral cordotomy), stimulation of inhibitory pathways (e.g. acupuncture, opioids), or alteration of emotional or behavioural response.

NSAIDs

NSAIDs are analgesic, anti-inflammatory and antipyretic. Act to inhibit cyclo-oxygenase in the spinal cord and periphery to decrease prostanoid synthesis and diminish post-injury hyperalgesia at these sites. NSAIDs reversibly inhibit cyclo-oxygenase to reduce prostaglandin and thromboxane synthesis (Fig. 10.4). Type 1 cyclo-oxygenase (COX-1) is present in gastric mucosa to produce protective prostaglandins and modulates renal function and platelet adhesiveness. Type 2 cyclo-oxygenase (COX-2) is responsible for inflammatory prostaglandins. Drugs which inhibit only COX-2 (rofecoxib, parecoxib) cause fewer gastric, renal and haemorrhagic side-effects. NSAIDs also inhibit neutrophil activation by inflammatory mediators and act centrally on the thermoregulatory centre. There is minimal protein binding with subsequent large volume of distribution.

Figure 10.4 Cyclo-oxygenase (COX) pathways.

Not generally as effective as opioids for acute pain, but reduce opioid requirements by 30–50%. May be useful in day-case surgery to avoid opioids.

Opioids

Pharmacology. Protein binding is a major determinant of drug distribution. Albumin binds acidic drugs (e.g. morphine); α₁ acid glycoprotein (AAG) binds basic drugs (e.g. fentanyl, alfentanil, sufentanil). Neonatal albumin and AAG levels reach adult levels by 1 year.

Opioid receptors are found in high concentrations in the limbic system and spinal cord:

These opioid receptors have recently been reclassified by the International Union of Pharmacology (IUPHAR) as OP₁ (δ), OP₂ (κ) and OP₃ (μ).

Actions

• Cardiovascular: ↓ SNS drive, direct effect on vagal nucleus to ↓ HR, direct effect on SA node

• Respiratory: ↓ rate, dyscoordination, respiratory depression mediated by μ receptors. CO₂ response curve shifted to right. Depression of cough reflex

• Analgesia

• Anxiolysis (shift towards δ rhythm on EEG)

• Euphoria/dysphoria

• Histamine release via opioid receptors on mast cells. Blocked by naloxone

• GI: smooth muscle spasm, ↓ lower oesophageal sphincter tone, nausea and vomiting

• Miosis via opioid receptors on Edinger–Westphal nucleus

• Hormonal effects via D₂ receptors in hypothalamus: ↑ ADH, ↑ GH, ↑ prolactin; ↓ ACTH, ↓ FSH, ↓ LH

• Muscle rigidity via (?) opioid receptors in substantia nigra.

Routes of administration. Up to eightfold variation in minimum analgesic blood levels between patients. Therefore, no one regimen is suitable for all patients.

Oral. Delayed postoperative gastric emptying results in delayed absorption followed by large bolus absorbed when motility returns. May be of more use in the late postoperative period once bowel motility returns.

Nausea and vomiting prevent oral intake. Poor bioavailability because of first pass.

Sublingual. Systemic absorption avoids first pass. Dry mouth reduces absorption.

PR. Systemic absorption avoids first pass. Not affected by GI motility or nausea and vomiting. Slow absorption delays onset.

Transdermal. Rate of absorption ∝ lipid solubility. Reduced absorption with vasoconstriction.

Inhalational. Used for relieving symptoms of dyspnoea and postoperative pain. Some lost on expiration, widely variable absorption, nasal pruritis and cough limit its clinical application.

Intra-articular. Action via intra-articular opioid receptors.

Intranasal. Rapid onset of lipid-soluble drugs. Systemic absorption avoids first pass. Useful route for postoperative pain in children.

Subcutaneous. Useful for pain relief in children since small cannulae can be inserted with minimal distress. Use with continuous infusion or intermittent bolus.

Intramuscular. Pain of injection, erratic uptake if poor tissue perfusion, wide fluctuations in blood levels and thus degree of analgesia and side-effects. Often administered too infrequently if ‘prn’.

Intermittent intravenous injections. Avoids pain of injection but has similar problems to i.m. route. Needs 1:1 nursing care to monitor respiratory depression.

Continuous intravenous infusion. May need initial i.v. bolus dose since steady state takes five half-lives to establish. More stable blood levels, but risk of insidious onset of respiratory depression and obstructive apnoea greater than that with PCA.

Patient controlled analgesia (Fig. 10.5).

Figure 10.5 Patient controlled analgesia with intramucular morphine.

Route of choice. Less overall opioid requirements than other routes. Patient acts as feedback to prevent overdose. Patients do not have to wait after onset of pain to receive analgesia, and immediate administration gives patients a greater sense of control. Requires loading dose and correct settings of lockout time (5–10 min), dose per bolus (morphine 0.01–0.025 mg/kg) and maximum dose/hour. Suitable for most children over 5 years. Background dose increases risk of respiratory depression and does not affect total dose. Fentanyl PCA reduces pruritis compared with morphine and may also be more appropriate in renal failure. Less incidence of respiratory depression (0.1–0.8.%) when compared with i.m. opioid boluses (0.2–0.9%) or i.v. opioid infusion (1.7%). Patient concerns regarding addiction and overdose may limit effective use.

Intrathecal/extradural. Most effective when combined with local anaesthetics. Side-effects are common, especially pruritis. Respiratory depression up to 24 h.

Fentanyl Patches: Serious and Fatal Overdose from Dosing Errors, Accidental Exposure, and Inappropriate Use

MHRA Guidance 2007

• Healthcare professionals, particularly those who prescribe fentanyl patches, must fully inform patients and caregivers about directions for safe use:

– Follow the prescribed dose

– Follow the correct frequency of patch application

– Ensure that old patches are removed before applying a new one

– Patches must not be cut

– Avoid touching the adhesive side of patches and wash hands after application

– Follow instructions for safe storage and disposal of used or un-needed patches.

• Increased body temperature, exposure of patches to external heat sources, and concomitant use of CYP3A4 inhibitors may lead to potentially dangerous rises in serum fentanyl levels. Concomitant use of other CNS depressants might also potentiate adverse effects from fentanyl

• Healthcare professionals, particularly those who prescribe fentanyl patches, should ensure that patients and caregivers are aware of the signs and symptoms of fentanyl overdose, i.e. trouble breathing or shallow breathing; tiredness; extreme sleepiness or sedation; inability to think, walk, or talk normally; and feeling faint, dizzy, or confused. Patients and caregivers should be advised to seek medical attention immediately if overdose is suspected. Patients who experience serious adverse events should have the patches removed immediately and should be monitored for up to 24 h after patch removal.

α₂-Agonists (e.g. clonidine)

α₂-adrenergic receptors are located at peripheral (primary afferent terminals), spinal (neurones in the superficial laminae of the spinal cord) and brainstem sites (brainstem nuclei) where they are involved in nociceptive modulation. α₂ adrenoceptors are devoid of respiratory depressant and addictive effects, but sedation and hypotension are limiting their clinical use as an effective analgesic agent.

α₂-agonists have the following characteristics:

NMDA receptor antagonists

NMDA receptors on the postsynaptic membrane of dorsal horn neurones are activated by glutamate to stimulate ascending pathways. Activation of NMDA receptors results in induction and maintenance of central sensitization during pain states. NMDA antagonists (especially those acting on the NR2β receptor subunit) may be useful in the treatment of chronic pain.

Ketamine blocks the open calcium channel of the NMDA receptor. Psychotomimetic side-effects, salivation and cardiac stimulation limit its use.

Gabapentin

Introduced for epilepsy in 1990s. High binding affinity for the α₂δ subunit of the presynaptic voltage-gated calcium channels, binding to which inhibits calcium influx and subsequent release of excitatory neurotransmitters in the pain pathways. At least as effective as morphine for postoperative analgesia and may also prevent opioid tolerance. May cause dizziness and somnolence.

Capsaicin receptor antagonists

Capsaicin is a vanilloid found in chilli peppers. Capsaicin activates the transient receptor potential ligand-gated ion channel family (TRPV1), as does heat, acidosis, cannabinoids and NADA (N-arachidonoyl-dopamine). Prolonged application of an agonist, e.g. capsaicin leads to release of central transmitters (glutamate and substance P) from nociceptive afferents and loss of function of the afferents due to exhaustion of neurotransmitters. This is the basis of the use of capsaicin cream where it has been shown to be of benefit in osteoarthritis, diabetic neuropathy, psoriasis and post-herpetic neuralgia.

The TRPV1 receptor may be upregulated in some disease states e.g. osteoarthritis, post-herpetic neuralgia, cancer-induced bone pain. TPRV1 antagonists may be an important new class of analgesic agents.