Figure 9-1. Descartes model of pain transmission in the peripheral nervous system.

        In 1645 Descartes proposed a mechanism for pain transmission, suggesting that a peripheral pain impulse was transmitted directly from the periphery to the brain by a “hard-wired” system without any intermediate modulation (Figure 9-1). This theory of pain transmission was widely held as true until as recently as 40 years ago.

        In 1965 Melzack and Wall proposed their groundbreaking gate-control theory of pain that suggested that pain could be modulated or “gated” at a number of points in the pain pathway. Subsequent research identified the dorsal horn (lamina II) of the spinal cord as an important site of potential modulation, and subsequent treatments for acute and chronic pain have utilized this knowledge to good effect. Treatments such as the use of spinal opioids and transcutaneous electrical nerve stimulation (TENS) have both been developed in the light of this knowledge. The gate theory also changed many (often unsuccessful) pain management strategies from techniques where we tried to ablate pain pathways either chemically or surgically to more recent modulation techniques where we attempt to inhibit excitatory influences and enhance inhibitory influences within the pain pathway.

        In the last few decades important advances have also occurred in our knowledge of how pain is generated and transmitted from the peripheral nervous system (PNS) to the central nervous system (CNS). Modulation of pain in the PNS also involves numerous transmitters and mechanisms that both excite and inhibit nociceptive pathways.

        In the PNS under normal physiologic conditions nociceptive signals are produced when A-α and C fibers are stimulated by heat, pressure, or several chemicals produced by tissue damage and inflammation (potassium, histamine, bradykinin, prostaglandins, adenosine triphosphate [ATP]) .² Nociceptive signals are transmitted to the superficial layers of lamina II of the dorsal horn in the spinal cord where they are modulated at both the presynaptic and postsynaptic level and also by excitatory and inhibitory descending control pathways form the brainstem (Figure 9-2)³. Signals that are successful in crossing this gate travel on to the brainstem and thalamus before reaching the cerebral cortex to produce a pain stimulus.

        A wide array of chemical mediators are produced in the the PNS and have both excitatory and inhibitory influences on peripheral sensory nerve transmission⁴ both in the acute and chronic phase of injury (Figure 9-3)⁵. These can directly activate the nerve (ATP, glutamate, 5-hydroxytryptamine [5-HT], histamine, bradykinin), enhance depolarization by sensitizing the nerve to other stimuli (prostaglandins, prostacyclin, and cytokines such as interleukins) or provide a regulatory role on the sensory neuron, inflammatory cells, and sympathetic fibers (bradykinin, tachykinin, and nerve growth factor).

        RATIONALE FOR USE OF ANALGESIC ADJUVANTS

As previously noted pain transmission in the central and peripheral nervous systems involves a complex array of neurotransmitters and pathways that are not easily blocked by one drug type or technique alone. A number of drugs in the anesthesiologist’s armamentarium, including opioids, nonsteroidalantiinflammatory drugs (NSAIDs), α2-agonists, and N-methyl-D-aspartate (NMDA) antagonists, have activity at these sites of action and may have benefit if applied in the PNS.

        This knowledge can aid the regional anesthesiologist in a number of ways:

Figure 9-2. The gate theory proposed that small (C) fibers activated excitatory systems (black neuron) that subsequently excited output cells—these latter cells had their activity controlled by the balance of large fibers (α-β)mediated inhibitions (mediated by endogenous opioids) and also by descending control systems from the central nervous system (mediated by norepinephrine and serotonin). (Reprinted, with permission, from: Dickenson AH: Gate control theory of pain stands the test of time. Br J Anaesth 2002;88:755-757.)

Figure 9-3. Excitatory and inhibitory influences on peripheral nerve activity by mediators released by tissue injury and inflammation and by a variety of agents acting on neuroreceptors. (Reprinted, with permission, from Sawynok J: Topical and peripherally acting analgesics. Pharmacol Rev 2003;55:1 -20.)

        OPIOID ANALGESICS

During inflammation, opioid receptors are expressed in peripheral sensory fibers and immune cells,⁶ moreover endogenous opioids are released from these cells and balance the increased nociceptive state produced by inflammation.⁷ An increasing body of work suggests an intimate relationship between endogenous opioids and the immune system. Christoph Stein and colleagues in Berlin have performed a number of pioneering studies^8,9 that describe the ability of the immune system to deliver endogenous opioids and the ability of inflammation to stimulate movement of opioid receptors to the site of injury, thereby allowing antinociception to occur. However these changes do not occur immediately after injury and can take up to 96 h to occur.¹⁰

        Opioid receptors and neuropeptides (eg, substance P) are synthesized in the dorsal root ganglion and transported along intraaxonal microtubules into central and peripheral processes of the primary afferent neuron (Figure 9-4). At the terminals, opioid receptors are incorporated into the neuronal membrane and become functional receptors. Upon activation by exogenous or endogenous opioids (released by immune cells), opioid receptors couple to inhibitory G-proteins. This leads to direct or indirect (through decrease of cyclic adenosine monophosphate) suppression of Ca²⁺ or Na⁺ currents and subsequent attenuation of substance P release. The permeability of the perineurium is increased within inflamed tissue, enhancing the ability of opioids to reach target receptors.

        Numerous studies have applied opioids in the PNS to either peripheral nerves or the intraarticular space. Although many studies claim an analgesic benefit of peripherally applied opioids, few studies incorporated a control group with a systemically applied opioid for comparison. Without inclusion of a control it is impossible to interpret whether the peripheral opioid is having a true peripheral effect or is instead being carried to the CNS to induce analgesia. True peripherally mediated opioid analgesia may be beneficial if this is associated with improved analgesia or reduced adverse effects compared with systemic administration. If the effect is mediated centrally then there is no clear benefit over systemic administration.

Figure 9-4. Opioid receptor transport and signaling in primary afferent neurons. (Adapted, with permission, from Stein C: Nature Med 2003;9(8):1003). OR = opioid receptor; sP = substance P, EO = exogenous opioids; OP = endogenous opioid peptides; G_i/o = inhibitory G proteins; cAMP = cyclic adenosine monophosphate.

Perineural Opioids

Opioid receptors identified on primary afferent fibers are transported from the dorsal root ganglion to the site of inflammation; however, while they are undergoing axonal transport they may not be easily reached by opioid agonists. This may explain the reason that two recent systematic reviews published in 1997 and 2000¹¹·¹² found little evidence for the benefit of adding opioids to local anesthetics in peripheral nerve blockade. An updated table of studies examining perineuronal administration of opioids^13–16 (excluding buprenorphine and tramadol) shows that analgesic benefit remains equivocal (Table 9-1). In addition Peng and Choyce¹⁷ reviewed the use of opioids in intravenous regional anesthesia (IVRA) with similar disappointing conclusions.

        Despite these disappointing results, the two opioid agonists that have demonstrated analgesic efficacy when administered perineuronally are buprenorphine and tramadol. Buprenorphine is a partial μ-receptor agonist with a very high receptor affinity compared with fentanyl (24-fold) or morphine (50-fold). In addition it has intermediate lipid solubility, which allows it to cross the neural membrane.^18–19

Candido and colleagues²⁰ added 0.3 mg buprenorphine (a partial opioid agonist) to a combination of mepivacaine and tetracaine in axillary block and found an almost 100% increase in the duration of analgesia compared with the administration of axillary block plus the same dose of intramuscular buprenorphine with no significant increase in adverse effects. This supports the peripheral analgesic effect of buprenorphine and also the earlier findings of two studies that examined buprenorphine without a systemic control group.^21,22 Studies examining buprenorphine are examined in greater detail in Table 9-2

    IM = intramuscular

Clinical Pearls

        Tramadol is a weak opioid agonist with some selectivity for the μ-receptor that also inhibits norepinephrine reuptake and stimulates serotonin release in the intrathecal space. Norepinephrine and serotonin are transmitters for the descending control pathway in the spinal cord and enhance analgesia.^23–24 Kapral and coworkers²⁵ used a 100-mg dose of tramadol as an adjuvant to mepivacaine in axillary brachial plexus block. They divided 60 patients into three groups, one group received mepivacaine 1% with 2 mL saline, the second group received mepivacaine 1% with 100 mg tramadol, and the third group received mepivacaine 1 % with 2 mL saline and 100 mg tramadol intravenously. This study demonstrated an increased duration of motor and sensory blockade in the axillary tramadol group that significantly (p < 0.01) outlasted both an intravenous and placebo group. Robaux and colleagues²⁶ subsequently performed a dose-response study with placebo, and 40-, 100-, and 200-mg doses of tramadol added to a fixed dose of mepivacaine 1.5% in axillary block and found that the 200-mg dose provided best analgesia with no increased adverse effects.

Clinical Pearls

Intraarticular Opioids & Other Peripheral Routes of Administration

Opioid agonists administered into inflamed tissue will bind to opioid receptors on sensory terminals and induce analgesia. Animal studies indicate that these peripheral opioid receptors are expressed 96 h after the initial inflammatory injury.¹⁰ Intraarticular (IA) administration of opioids will therefore only produce analgesia in patients with preexisting inflammation. Kalso and coworkers²⁷ systematically examined the role of IA opioids in 1997 and established that there existed evidence for a prolonged benefit from IA morphine without significant adverse effects, at doses of 1 to 5 mg. No dose response was detected. Recent articles support this finding and show the benefit of IA morphine^28,29 tramadol,³⁰ buprenorphine³¹ and sufentanil.³²

Clinical Pearls

        A recent interesting study by Reuben and colleagues³³ investigated the use of morphine (5 mg) injected into the iliac crest bone graft donor site during cervical spine fusion surgery. Morphine significantly reduced both acute pain and the incidence of development of chronic pain (assessed 1 year after surgery) compared with patients who had intramuscular morphine or placebo (5% vs 37 and 33%).

Clinical Pearls

        I ALPHA₂-AGONISTS & CLONIDINE

Clonidine is an α₂-agonist with some α₁ -stimulatory effects. It has traditionally been used as an antihypertensive agent and has been noted to have sedative and analgesic effects for many years. More recently it was determined that α₂-receptors exist in the dorsal horn of the spinal cord, and stimulation of these receptors produces analgesic effects by inhibiting the presynaptic release of excitatory transmitters, including substance P and glutamate.^34–36 Intrathecal clonidine mediates analgesia by increasing acetylcholine levels, which in turn stimulates muscarinic receptors. Muscarinic excitation increases Γ-amino butyric acid levels onto the primary afferent fiber inhibiting the release of the excitatory neurotransmitter, glutamate.³⁷

        Clonidine injected close to peripheral nerves with or without local anesthetic drugs appears to mediate analgesia in a number of ways. Clonidine has local anesthetic properties³⁸ and tonically inhibited compound action potentials of C fibers greater then A-α fibers in rat sciatic nerve and was comparable to lidocaine in its ability to inhibit C fibers in rabbit vagus nerve.^38,39 Clonidine also has a pharmacokinetic effect on local anesthetic redistribution mediated by a vasoconstrictor effect at the α₁ -receptor.⁴⁰ Recent animal models have demonstrated and supported earlier work that clonidine predominantly facilitates peripheral nerve block through hyperpolarization-activated cationic current and that this effect is independent of any vasoconstrictor effect.⁴¹

        A more recent addition to the selection of α₂-agonists is dexmedetomidine, which is selective for the α₂-receptor and which at present is mainly studied as a sedative agent in intensive care units. Dexmedetomidine may be expected to produce more profound analgesia but also greater adverse effects because of the selectivity of action.

        Stimulation of the α₂-receptor produces hypotension, bradycardia, and sedation at higher doses, and these effects may outweigh any analgesic benefits produced by the use of these agents.

Perineuronal Application

Over 30 studies in humans are now examining the effect of clonidine on local anesthetics in peripheral nerve block. There is good evidence from these studies that clonidine in doses up to 1.5 mcg/kg prolongs sensory block and analgesia when administered with local anesthetics for peripheral nerve block. This supports the early opinion of Murphy and collaegues¹² that clonidine is a beneficial adjuvant when added to peripheral nerve block and that the effect is most likely mediated in the PNS.

        Although a number of studies are examining the effect of clonidine added to peripheral nerve block, only a few have controlled for a systemic effect of clonidine. Singelyn and coworkers⁴² evaluated 30 patients receiving an axillary brachial plexus block with 40 mL of 1% mepivacaine plus epinephrine 5 mcg/mL. Patients were randomized to three groups and received: (1) local anesthetic alone, (2) local anesthetic plus 150 meg of clonidine administered subcutaneously, or (3) 150 meg of clonidine in the brachial plexus block with local anesthetic. Clonidine added to the axillary brachial plexus block delayed the onset of pain twofold, without adverse effects when compared with systemic control. Hutschala and coworkers⁴³ have recently demonstrated the peripheral analgesic effect of clonidine in volunteers when added to brachial plexus block with 0.25% bupivacaine. However, other recent studies demonstrate no overall benefit of adding clonidine to long-acting local anesthetics such as bupivacaine and ropivacaine.⁴⁴

        The addition of clonidine to continuous peripheral nerve blocks is not beneficial. Ilfeld and colleagues^45,46 have demonstrated in two studies that both 0.1 and 0.2 mcg/mL of clonidine added to continuous infusion of ropivacaine 0.2% failed to reduce pain scores or oral analgesic use after upper extremity surgery.

Clinical Pearls

Related posts:

Regional Anesthesia in the Patient with Preexisting Neurologic Disease. The History of Local Anesthesia. Stimulating Catheters. Ultrasound-Assisted Nerve Blocks in Adults. Cutaneous Blocks for the Upper Extremity. Supraclavicular Brachial Plexus Block.