Opioid analgesics are widely used drugs for the management of both acute and chronic pain. Side effects of opioids often limit their dynamic range. The reality of drug dependence, misuse, and abuse makes consideration of in which populations they should be used and for which indications critical. There are several centrally acting nonopioid analgesic adjuvants whose efficacy is supported by scientific evidence. Adding nonnarcotic medications as part of multimodal analgesia is appealing. These agents relieve pain by mechanisms unrelated to opioid receptors; they do not cause respiratory depression, physical dependence, or abuse, and are not regulated under the Controlled Substances Act.
In order to minimize the adverse effects of opioid analgesic medications, anesthesiologists and surgeons are increasingly turning to nonopioid analgesic techniques as adjuvants for managing pain during the perioperative period. Neuraxial drug administration is a group of techniques that deliver drugs in close proximity to the spinal cord, that is, intrathecally into the cerebrospinal fluid (CSF) or epidurally into the fatty tissues surrounding the dura, by injection or infusion. The administration of centrally acting agents bypasses the blood–brain barrier resulting in much higher CSF concentrations while using reduced amounts of medication to achieve equipotent effect.
The addition of neuraxial nonopioid adjuvants to local anesthetics may improve the quality of analgesia. Nonopioid neuraxial adjuvants have a number of different mechanisms of action that are described in the paragraphs that follow. Potential advantages of these agents include a reduction in the dose of individual drugs, a reduction in opioid requirements, and potentially, a reduction in opioid-related side effects. However, the reduction in severe opioid-related side effects is seldom documented as the most severe side effects such as respiratory depression are rare. Adjuvant drugs have their own side effects which at best do not augment opioid side effects. Neuraxial administration of medications confers an inherent risk of injury to structures of the nervous system, not only by the needles and catheters used but also by neurotoxic effects of the compounds injected. Therefore, the potential neurotoxicity of any drug used in this setting requires careful study.1
In principle, any drug considered for intrathecal administration in humans requires histologic, physiologic, and behavioral testing in a number of animal species before clinical trials. Most drugs have not been sufficiently well studied to recommend their neuraxial use. Many drug preparations also contain antioxidants, preservatives, and excipients, which might contribute to neurotoxicity. It is important to note that the U.S. Food and Drug Administration (FDA) has not approved neuraxial (epidural or subarachnoid) administration of most of the drugs listed in this chapter for routine clinical use. Nonetheless, many of these agents have undergone extensive study and in many cases that has included the requisite toxicity studies.
α2-Adrenergic Agonists
Epidural or intrathecal administration of α2-adrenergic agonists provides analgesia by activating α2-adrenergic receptors (G protein–coupled inhibitory receptors) on the sympathetic preganglionic neurons that mediate a reduction in norepinephrine release (via a negative feedback mechanism). Descending noradrenergic pathways, originating in nuclei A5 and A7 in the pons and midbrain appear to play a major inhibitory role on sympathetic preganglionic neuron activity.2 The overall effect is sympatholysis resulting in analgesia, hypotension, bradycardia, and sedation.3,4
Clonidine
Clonidine acts as a selective partial α2 receptor agonist. Neuraxial clonidine has been shown to be an effective analgesic for chronic cancer and noncancer pain, as well as for postoperative pain. Clonidine has antihypertensive effects and it has been shown to potentiate postoperative analgesia induced by local anesthetics. Spinal clonidine causes a 30% prolongation of sensory and motor block of local anesthetics. Clonidine is commonly administered epidurally in doses ranging from 75 to 150 µg. The doses used for intrathecal (spinal) analgesia ranges from 10 to 50 µg. For caudal analgesia, clonidine is administered as 1 µg/kg dose.
Intrathecal administration of clonidine 37.5 to 150 µg with bupivacaine results in a dose-dependent increase in sensory blockade and more pain-free intervals in the postoperative period. An intrathecal dose of 150 µg was noted to be associated with motor blockade.4 With combined spinal/epidural anesthesia, intrathecal clonidine doses as low as 15 µg resulted in an increased duration of anesthesia, analgesia, and motor blockade.
Epidural clonidine in the postoperative period reduced visual analog scale (VAS) score and also decreased morphine consumption. Addition of clonidine intrathecally or epidurally was associated with significant reduction of heart rate and blood pressure.5 Epidural clonidine 1 µg/mL when added to morphine 0.1 mg/mL in 0.2% ropivacaine significantly reduced postoperative pain scores of total knee arthroplasty patients.
Neuraxially administered opioids and α2 agonists exhibit synergism.3 The addition of clonidine to opioids for postoperative analgesia as a continuous epidural infusion reduces opioid requirements by 20% to 60%.6 The addition of 75 µg clonidine to epidural ropivacaine results in longer and more effective analgesia for cesarean delivery. Clonidine is a useful adjunct for labor epidural analgesia. It has been shown to reduce local anesthetic requirements and improve pain scores when combined with 0.125% bupivacaine with or without fentanyl 2 µg/mL. When used in a concentration of 1 to 2 µg/mL, clonidine has no significant effects on fetal heart rate, Apgar scores, or umbilical cord gases. Clonidine may also have additional beneficial effects in women with preeclampsia. However, the FDA has issued a black box warning concerning the use of neuraxial clonidine in obstetric anesthesia because of related maternal hemodynamic instability. The warning states, “Obstetrical, Postpartum, or Perioperative Use: weigh risk/benefit; epidural clonidine generally not recommended for obstetrical, postpartum, or perioperative pain management due to risk of hemodynamic instability, esp. hypotension and bradycardia.” As such, the benefit of adjuvant analgesia and potentially favorable hemodynamic effects must be weighed against the risks for each individual patient.
Neuraxial clonidine is indicated for the treatment of intractable pain in cancer patients unresponsive to maximum doses of opioids. This formed the basis for the approval of epidural clonidine by the FDA.7 Its use as an adjunct has been most widely accepted in pediatric anesthesia, as a means of increasing the duration of analgesia from caudal block, and to a lesser extent in obstetric anesthesia, to provide analgesia in labor.8
Intrathecal clonidine appears to have antihyperalgesic properties.3,8–11 As hyperalgesia is the physiologic expression of central nervous system (CNS) sensitization, it may be useful in preventing the increased risk or central sensitization and development of persistent pain after surgery in patients with severe postoperative pain.12
A recent systematic review aimed to quantify beneficial and harmful effects of clonidine when used as an adjuvant to intrathecal local anesthetics for surgery concluded that clonidine prolongs the regression of the sensory block in a dose-dependent manner, prolongs the time to the first request of an analgesic, and the duration of complete motor block, with weak evidence of dose-responsiveness. In addition, clonidine decreases the risk of intraoperative pain and increases the risk of arterial hypotension, without evidence of dose-responsiveness. Finally, clonidine has no relevant impact on the time to achieve complete sensory or motor block, on the extent of the cephalad spread of the sensory block, or on the risk of bradycardia.13
Dexmedetomidine
Dexmedetomidine has a higher affinity for α2 receptors than clonidine and is associated with a fewer hemodynamic and systemic side effects at equivalent doses. Evidence indicates that neuraxial administration of dexmedetomidine produces spinal analgesia as efficiently as clonidine.14–16 A dose of 3 µg of intrathecal dexmedetomidine was found to be equipotent with 30 µg of clonidine.17 Intrathecal dexmedetomidine 5 µg and fentanyl 25 µg were compared for vaginal surgeries with bupivacaine anesthesia. Dexmedetomidine caused significantly longer sensory and motor blockade.18
Epidural dexmedetomidine exhibits synergism with local anesthetics, increasing the density of motor block, prolonging the duration of both sensory and motor block, and improving postoperative analgesia. Clinical studies exhibit potentiation of neuraxial local anesthetics, decrease in intraoperative anesthetic requirements with prevention of intraoperative awareness, and improved postoperative analgesia when epidural dexmedetomidine was used in conjunction with general anesthesia.7,14–16,19,20 The addition of 2 µg/kg dexmedetomidine epidurally prolongs the duration of analgesia and decreases the requirement for rescue analgesics in patients undergoing lower limb orthopedic surgery, abdominal surgeries, and cesarean section which was associated with a significant fall in heart rate and mean arterial blood pressure. In thoracic surgery, the use of epidural dexmedetomidine decreases the anesthetic requirements, prevents awareness during anesthesia, and improves intraoperative oxygenation and postoperative analgesia.21Caudal dexmedetomidine in a dose of 2 µg/kg with bupivacaine used in pediatric patients undergoing hernia repair or orchiopexy was found to cause more sedation, prolonged analgesia, less anesthetic consumption, and less irritability. There were no hemodynamic differences when compared to patients who had received only bupivacaine.22–24
No neurotoxicity has been reported to date in studies in both humans and animals during intrathecal or epidural administration of dexmedetomidine. However, there is some evidence from animal studies of demyelination of the oligodendrocytes in the white matter, suggesting harmful effects on the myelin sheath when administered via the epidural route. Advanced pathologic investigations are required to establish the safety of α2-adrenergic agonists. Nevertheless, the major side effects of α2-adrenergic agonists are limited to hemodynamic effects (i.e., bradycardia and hypotension).
Neostigmine
Neostigmine acts by inhibiting acetylcholinesterase and preventing the breakdown of acetylcholine. Naguib and Yaksh3,25 demonstrated that the intrathecal administration of cholinesterase inhibitors (neostigmine or edrophonium) produces a dose-dependent antinociceptive activity in rats (Fig. 8-1). These antinociceptive effects are independent of opioid and α2-receptor systems and are primarily due to stimulation of muscarinic (but not nicotinic) cholinergic receptors. The use of intrathecal acetylcholinesterase inhibitors, such as neostigmine, results in analgesia in both preclinical and clinical models. Neostigmine is a hydrophilic molecule, like morphine, and when applied to the epidural space, it requires time for diffusion through the dura mater into the subarachnoid space.26,27
Intrathecal neostigmine has been used as an adjunct to intrathecal local anesthetic or opioid to prolong regional analgesia and improve hemodynamic stability, with variable results. Escalating doses of intrathecal neostigmine (10 to 100 µg) followed by 2% epidural lidocaine resulted in improved analgesia in a dose-independent manner after cesarean delivery.28 The reduction in morphine requirements lasted up to 10 hours without adverse fetal effects, but the incidence of nausea varied from 50% to 100% in patients. In another study, intrathecal neostigmine (10 µg) alone was ineffective for labor pain relief, but when combined with intrathecal sufentanil, reduced the ED50 of sufentanil by approximately 25%.29
Epidural administration of neostigmine (100 to 200 µg) appears to avoid these clinically troublesome adverse effects while still improving local anesthetic-induced analgesia.30,31 Combinations of epidural neostigmine with local anesthetics, opioids, or clonidine for labor analgesia displayed analgesic effectiveness, potentiating the analgesic effect of opioids and clonidine.32–34 Epidural neostigmine does not affect motor blockade. Higher doses of intrathecal neostigmine can cause mild sedation.27,35
A meta-analysis evaluated the effectiveness and side effects of intrathecal neostigmine in the perioperative and peripartum settings. The authors concluded that adding intrathecal neostigmine to other spinal medications improves perioperative and peripartum analgesia marginally when compared with placebo. It is associated with significant side effects and the disadvantages outweigh the minor improvement in analgesia achieved.36 Nausea and vomiting were seen less frequently in epidural neostigmine studies. This is thought to be due to the lower amount of neostigmine that reaches the CSF and the absence of cephalic distribution.37 Neostigmine stimulates muscarinic receptors in the bronchial smooth muscles and leads to bronchospasm. In intrathecal neostigmine studies, except at very high doses (e.g., 750 µg), no change has been detected in oxyhemoglobin saturation and in end-tidal carbon dioxide levels.38
Intrathecal neostigmine at a dose of 1 µg/kg has been used in pediatric lower abdominal and urologic surgeries where it was found to increase analgesia.39,40 Adverse gastrointestinal effects have made neostigmine an unpopular choice for neuraxial adjuvant therapy. Unlike intrathecal neostigmine, epidural neostigmine is not associated with an increased risk of nausea and vomiting; however, doses greater than 100 µg have been associated with sedation. It does not cause respiratory depression or pruritus either alone or in combination with neuraxial opioids.
Ketamine
Anesthetic and subanesthetic doses of ketamine have analgesic properties as a result of noncompetitive antagonism of N-methyl-D-aspartate (NMDA) receptors. With prolonged, repetitive nociceptive stimulation, NMDA receptors are activated, releasing excitatory neurotransmitters glutamate, aspartate, and neurokinin.41 Its primary analgesic effect is mediated by antagonizing NMDA receptors located on secondary afferent neurons in the dorsal horn of the spinal cord thus preventing enhancement of excitatory neurotransmission. These neurotransmitters are associated with many activities including central sensitization, wind-up, and the plasticity of various systems such as memory, vision, motor function, and spinal sensory transmission.
Neuraxial ketamine must be administered in a preservative-free solution to avoid neurotoxic effects.42–45 Naguib et al.46 studied epidural doses of 10 mg and 30 mg of ketamine and found that a 30-mg dose produced excellent postoperative pain relief. A low dose of ketamine at 4, 6, and 8 mg epidurally was found to be ineffective for postoperative analgesia.47,48 Caudally administered ketamine 0.5 mg/kg along with 0.175% levobupivacaine 1 mL/kg has been used successfully without adverse effects in children for lower abdominal and urologic surgeries.49 Epidural infusion of 0.25 mg/kg per hour of S(+)-ketamine during thoracic surgery provides better postoperative analgesia than epidural 0.25% ropivacaine (Fig. 8-2).50 Both epidural infusions were started before skin incision and were run at 6 mL per hour for the duration of surgical procedure in the previously cited studies.
Combination of epidural ketamine with local anesthetic and/or opioid infusions results in improved analgesia without significantly increasing adverse effects.1,51,52 A bupivacaine-ketamine mixture provided better analgesia than bupivacaine alone (Fig. 8-3).51 Side effects such as motor weakness or urinary retention were not observed in the ketamine group.51 Adding low-dose ketamine to a multimodal epidural analgesia regimen provides better postoperative analgesia and reduces morphine consumption in thoracic, upper abdominal surgery, and lower abdominal surgeries.50 Ketamine acts synergistically with opioid, dopaminergic, serotoninergic, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonists to produce dissociation between the thalamocortical and limbic systems. AMPA is a non-NMDA-type ionotropic glutamate receptor that mediates fast synaptic transmission in the CNS. Ketamine has also shown efficacy in the management of neuropathic pain, and it is believed to work through one or more of these mechanisms. In high doses, ketamine may have additional minor analgesic effects by modulating descending inhibitory pathways through inhibition of reuptake of neurotransmitters.
Reported side effects of epidural ketamine include sedation, headache, and transient burning back pain during injection with doses greater than 0.5 mg/kg. There has been no reported respiratory depression, hallucinations, cardiovascular instability, bladder dysfunction, or neurologic deficit with epidural doses up to 1 mg/kg. The incidence of nausea, vomiting, and pruritus when combined with neuraxial opioids is similar to that reported with neuraxial opioid alone.
There are limited human studies on the use of intrathecal ketamine due to the potential risk of neurotoxicity from its preservative benzalkonium chloride. Intrathecal ketamine has been shown to decrease morphine requirements in patients with terminal cancer and is useful in opioid-tolerant patients. The intrathecal administration of ketamine, however, did not prolong or improve the quality of anesthesia from bupivacaine, but increased adverse effects.41Ketamine has been administered intrathecally to 16 patients with war injuries of the lower limbs in varying doses from 5 to 50 mg in a volume of 3 mL of 5% dextrose.53 In these doses, intrathecal ketamine resulted in a distinct sensory level in all patients and satisfactory surgical analgesia. Central effects (drowsiness, dizziness, and nystagmus) occurred in nine patients, but they remained conscious throughout; one patient experienced no central effects, and one patient developed dissociative anesthesia. Ketamine alone did not produce motor block, but addition of epinephrine resulted in complete motor block and may have intensified sensory blockade.53
The advantage of intrathecal ketamine is the lack of cardiovascular effects and respiratory depression. The main drawbacks of intrathecal ketamine are the potential for psychomimetic reactions, inadequate motor blockade, and short duration of action. Clinical manifestations of myelopathy suggestive of spinal cord injury were observed in a terminally ill cancer patient after continuous infusion intrathecal preservative-free ketamine at a rate of 5 mg per day for a duration of 3 weeks.54
Midazolam
Intrathecal midazolam produces analgesia by acting on γ-aminobutyric acid (GABA)-A receptors and reducing spinal cord excitability. GABA-A receptors are ligand-gated receptors located throughout the CNS and GABA is a major inhibitory neurotransmitter of the CNS, although glycine is prominent in the spinal cord. GABA binding results in a change of receptor configuration, causing an ion channel to open which allows chloride ions to flow down their electrochemical gradient into the cell. This results in hyperpolarization of the neuron and reduced action potential propagation.
A high density of benzodiazepine receptors (GABA-A) have been found in lamina II of the dorsal horn of the spinal cord, suggesting a possible role in pain modulation. Benzodiazepines have also been shown to act at opioid receptors.55 The δ-selective opioid antagonist, naltrindole, suppresses the antinociceptive effect of intrathecal midazolam, suggesting that intrathecal midazolam is involved in the release of endogenous opioid acting at spinal δ receptors.56 The substantia gelatinosa of the dorsal horn of the spinal cord contains a high density of GABA-A receptors. Benzodiazepines are likely to mediate their analgesic effect by increasing inhibition of nociceptive neurons in this area.
Midazolam administered epidurally57–61 or intrathecally55,62–67 has been shown to have an analgesic effect (Fig. 8-4). Adding midazolam (10 to 20 mg for 12 hours) to continuous epidural infusion of bupivacaine (100 mg) for postoperative pain provided better analgesia than bupivacaine alone without sedative effects.26,68,69
Midazolam added to fentanyl-ropivacaine epidural analgesia was associated with a significant reduction in the incidence of postoperative nausea and vomiting compared with fentanyl-ropivacaine alone, and a significant decrease in the amount of patient-controlled epidural analgesia (PCEA) administered without a significant increase in adverse events in these patients who underwent subtotal gastrectomy and postcesarean delivery. The exact mechanism by which midazolam exerts its antiemetic action is not fully understood. Postulated mechanisms include glycine mimetic inhibitory effects, enhancement of the inhibitory effects of GABA, inhibition of dopamine release, and augmentation of adenosine-mediated inhibition of dopamine in the chemoreceptor trigger zone.68–70 No sedation is observed at doses of 1 and 2 mg of epidural midazolam; however, sedation has been reported at higher doses.
Animal study has shown synergism between intrathecal midazolam and morphine.71 Subsequent clinical studies have evaluated intrathecal and epidural midazolam for treatment of postoperative and chronic pain.72 Intrathecal midazolam has also been investigated in combination with an opioid for labor analgesia.64 These studies support the analgesic efficacy of intrathecal midazolam at doses <2 mg and in concentrations <1 mg/mL. Intrathecal midazolam is more effective for treatment of somatic pain than visceral pain.72 The addition of intrathecal midazolam also decreases postoperative analgesic requirements. The incidence of postoperative nausea and vomiting is much less with intrathecal midazolam than that seen with intrathecal fentanyl.73 Midazolam can be successfully combined with other drugs such as opioids and clonidine for additive effects66 and has been used as a continuous infusion (12 mg per day) in patients with refractory pain.62
A serious risk of intrathecal drug administration is neurotoxicity and such neurotoxic effects have been demonstrated in animal studies. Most animal studies examining intrathecal administration of midazolam have demonstrated no neurotoxic effects, although two of the earliest studies reported signs of neurotoxicity. Current evidence suggests that the addition of midazolam in doses of 1 to 2 mg intrathecally is beneficial in the treatment of perioperative and chronic pain. Current evidence supports the use of midazolam in doses not exceeding 1 to 2 mg at concentrations not exceeding 1 mg/mL. Considerable experience in humans with the use of perioperative midazolam suggests no evident deleterious neurologic effects under these conditions.63,74–76 The story of the experimental work on intrathecal midazolam in animals and humans is a cautionary tale in drug development. Investigators proceeded with clinical trials in humans at a time when the only available animal data suggested that intrathecal administration of midazolam might well be neurotoxic. Only after the human trials were performed did additional animal data emerge to support the lack of neurotoxicity,74 raising significant ethical concerns about the progression of investigational work from animals to humans.
Tramadol
Tramadol is an analgesic combining mainly µ-opioid and monoaminergic activity through the inhibition of the neuronal uptake of serotonin and norepinephrine.77 Animal studies have confirmed the analgesic effect of intrathecally administered tramadol. However, there is limited available data in humans. Epidural administration of tramadol has been the subject of some study78–81 and did not demonstrate effective postoperative analgesia with epidural administration.82,83
The effect of intrathecal administration of tramadol to patients showed contradicting results.84–86 Tramadol 1 to 2 mg/kg has also been administered caudally in children for postoperative analgesia.87
Droperidol
Epidural droperidol is effective for reducing pruritus and postoperative nausea and vomiting.88 Long-term administration of intrathecal droperidol proved to be an excellent antiemetic in patients with nonmalignant pain.89 It has been suggested that droperidol exerts direct actions on the brainstem chemoreceptor trigger zone. Although no side effects were observed, it is important to recognize the lack of laboratory data documenting the safety of neuraxial droperidol (including the potential for neurotoxicity).90
Adenosine
In the spinal cord, adenosine receptors are located in the superficial layers of the dorsal horn. Adenosine shows antinociceptive activity at adenosine A1 receptors located in laminae I and II of the dorsal horn of the spinal cord.91Another proposed mechanism is enhancement of spinal norepinephrine release.92
Initial studies confirmed relative safety of intrathecal administration of adenosine in human volunteers with no reported clinical toxicity.93,94 Intrathecal adenosine does not inhibit acute pain95 but is effective in treating allodynia and hyperalgesia. Experimental hyperalgesia and allodynia is reduced by intrathecal adenosine in a non–dose-dependent fashion96; however, in clinical settings, it did not change the anesthetic requirement or postoperative analgesia.97 Similarly, in combination with an opioid, intrathecal adenosine did not prolong analgesia during labor.98
Adenosine appears be effective in the treatment of neuropathic pain. Intrathecal adenosine is not associated with hypotension, motor blockade, or sedation. Following many clinical trials involving animal subjects, intrathecal adenosine 500 to 2,000 µg in human volunteers was shown to decrease allodynia in phase I clinical trials. The only side effect observed was transient lumbar pain after a dose of 2,000 µg.99–101 The role of neuraxial adenosine in the armamentarium for treatment of acute or chronic pain awaits further delineation.
Conopeptides
Ziconotide
Ziconotide is a synthetic 25-amino acid, polybasic peptide with three disulfide bridges and is a derivative of an omega conotoxin found in the venom of the marine snail conus magnus. Ziconotide acts as a selective antagonist of neuronal (N-type) voltage-sensitive calcium channels within presynaptic neuronal terminals in the dorsal horn, thereby inhibiting nerve transmission. Ziconotide directly inhibits norepinephrine release and functions as a sympatholytic, resulting in decrease in mean and diastolic pressure, most profoundly when administered intravenously and normally negligible when dosed intrathecally.
Highly polar and water soluble, ziconotide is hypobaric at clinically useful concentrations and has a relatively large molecular weight. This agent has narrow therapeutic window, with neuropsychiatric side effects appearing in nearly all patients at higher doses or when dose escalation is too rapid. Initial infusion rates should be limited to 0.1 µg per hour with stepwise increase of this rate over time; CNS adverse effects are to be expected.102–104 Ziconotide is the only FDA-approved, nonopioid approved for intrathecal administration for the treatment of neuropathic pain.
Ziconotide produces marked spinal antinociception in animal models of acute and persistent pain105 and additional reports described its intrathecal administration to relieve severe neuropathic pain.106–109Following extensive demonstration of safety in animal models, clinical trials in humans suffering with poorly controlled pain associated with advanced illness demonstrated that side effects occurred in the majority of patients (92.9%).110 Significant adverse events reported in the ziconotide group were dizziness, confusion, ataxia, abnormal gait, and memory impairment. Suicidality was increased with ziconotide as compared to placebo. Most of the side effects are self-limiting with cessation of therapy. The marked expense and nearly universal appearance of side effects in those receiving ziconotide have limited the use of this agent in clinical practice. A small number of patients with chronic pain gain significant, ongoing pain reduction with few or tolerable side effects when receiving intrathecal ziconotide infusions via chronic, implanted intrathecal drug delivery systems.
Other Investigational Conopeptides
Xen 2174
Xen 2174 is a conopeptide derived from a marine snail. The drug is found to inhibit norepinephrine transport and activate noradrenergic inhibitory pathways causing antihyperalgesic, antiallodynic, and antinociceptive effects.111
CGX-1160
CGX-1160 is a conopeptide that produces analgesia by activation of neurotensin receptor type 1 (NTR1). The drug has been found to be safe in a small number of patients with neuropathic pain related to spinal cord injury.112
The therapeutic index of these newer conopeptides may well be superior to that of ziconotide, but much additional investigational work is needed before they can reach clinical use. The promise of a novel nonopioid analgesic with significant efficacy in the treatment of neuropathic pain remains elusive but is the most alluring promise of this novel class of analgesics.
Octreotide
Octreotide is a synthetic octapeptide of the somatostatin derivative of human growth hormone. Octreotide administered spinally causes analgesia.113,114 Intrathecal octreotide administered in an uncontrolled study to cancer patients for 5 years reduced pain without any adverse effects.115 One prospective double-blind study involving 20 human subjects showed an absence of safety signals with intrathecal octreotide at a dose of 20 µg per hour.116 The role of this agent in clinical practice remains undefined.
Baclofen
GABA acts as an inhibitory neurotransmitter in the CNS. Baclofen is an agonist of the GABA-B receptor. Baclofen suppresses neuronal transmission in the cerebral cortex, basal ganglia, thalamus, cerebellum, and spinal cord. The analgesic effects of baclofen are mediated postsynaptically via activating the G protein–linked GABA-B receptors in laminae II and III that result in increased potassium conductance and membrane hyperpolarization. Baclofen also acts presynaptically to inhibit Ca+2 conductance and, therefore, the release of glutamate and substance P, and postsynaptically to produce membrane hyperpolarization by increased potassium conductance through a G protein and second messenger system.117
Baclofen has low lipid solubility and low molecular weight makes it an appropriate candidate for spinal action when delivered by the epidural route, but there has been little meaningful study to date. Intrathecal baclofen has demonstrated efficacy in chronic pain syndromes associated with multiple sclerosis and complex regional pain syndrome (CRPS) type I. For somatic pain, intrathecal baclofen has been used for the treatment of low back pain with root compression syndromes.118 Intrathecal baclofen is specifically used for spasticity and dystonia due to various conditions such as cerebral palsy and spastic posttraumatic spinal cord injury. Recent interest has also focused on its use as an analgesic.117
A typical intrathecal dose of baclofen is 25 to 200 µg per day through a programmable intrathecal pump. Intrathecal administration is superior to systemic administration with regard to efficacy and adverse effects.119 Baclofen has also been observed to relieve central pain syndromes in patients with spasticity,120 although it is uncertain whether this is primarily an effect on musculoskeletal pain because of reduced spasticity or a direct analgesic effect.121Some evidence suggests efficacy against nociceptive and neuropathic pain, particularly when used in combination with morphine and/or clonidine.
Baclofen has been investigated in the perioperative setting in a randomized, double-blind study for total knee arthroplasty as an adjuvant with spinal bupivacaine in a 100 µg single dose. The results showed a statistically significant reduction in opioid use in the postanesthesia care unit (PACU), lower pain scores for 48 to 72 hours postoperatively, and a lower severity of pain at 3 months after total knee arthroplasty in patients who received intrathecal baclofen compared to those who received spinal bupivacaine and saline.122 Common side effects of baclofen include sedation, drowsiness, headache, nausea, and weakness. More serious side effects such as rhabdomyolysis and multiple organ failure have also been reported.123,124 Like many of the other adjuvant analgesics discussed in this chapter, the role for intrathecal baclofen in the perioperative treatment of pain requires further study.
Calcitonin
Calcitonin is a naturally occurring hormone that has been recently demonstrated to reduce pain, independent of its peripheral action at bony sites. The epidural and intrathecal dose is 100 International Unit. There have been a few studies on its use as an analgesic in the literature.125 Intrathecal administration of calcitonin is associated with side effects such as nausea and vomiting and nervousness; these were observed in a small number of calcitonin-treated patients. Postoperative nausea and vomiting occurred in 30% of patients who were provided with calcitonin mixed with bupivacaine.126
Cyclooxygenase Inhibitors
Ketorolac
Constitutive expression of cyclooxygenase (COX)-1 and COX-2 in the spinal cord, upregulation of cycloxygenase-1 and 2, and release and production of spinal prostaglandins occur after peripheral tissue injury. Intrathecal injection of prostaglandins causes hyperalgesia and allodynia.127,128 Ketorolac is a COX inhibitor. The intrathecal delivery of COX inhibitors theoretically would reduce pain and central sensitization. Targeted inhibition of spinal COX may be a viable strategy for treating pain. This has led many investigators to postulate that neuraxial administration of nonsteroidal antiinflammatory drugs (NSAIDs) produces analgesia following excitatory input into the spinal cord.129,130
The pharmacokinetics of ketorolac in CSF obtained from dogs suggests rapid elimination and delayed tissue uptake; therefore, continuous infusion of intrathecal ketorolac may be a more effective strategy. Animal data appear promising and healthy volunteer studies have not identified any adverse neurologic side effects. Understanding the relevance of these observations to pain in humans has been hampered by lack of regulatory approval for intrathecal injection of these products.74,76,101,131 Intrathecal injection of ketorolac was studied in humans in an open label, dose escalating safety study. Intrathecal ketorolac 0.25 to 2.0 mg was well tolerated, with the only adverse effect being a mild reduction in heart rate 15 to 60 minutes following injection.127 Intrathecal ketorolac did not relieve chronic pain or extend anesthesia or analgesia from intrathecal bupivacaine administered at the beginning of surgery.127
These studies suggest that spinally produced prostaglandins may have a more limited role in pain and hypersensitivity in humans than predicted by animal studies, and intrathecal ketorolac may have limited analgesic effects in humans but could be active in states of central sensitization, including postoperative and chronic pain.
Gabapentin
Gabapentin acts on voltage-dependent calcium channels and inhibits glutamate release at the dorsal horn of the spinal cord. Oral gabapentin is approved as an anticonvulsant medication that demonstrated some efficacy in treating neuropathic pain.132,133 Given the fact that gabapentin is not well absorbed from the gastrointestinal system and penetrates the blood–brain barrier poorly, its nonopioid properties and presumed spinal site of analgesic action made the study on intrathecal gabapentin attractive. However, a trial of extended (22 days) infusion of intrathecal gabapentin did not demonstrate statistically significant or clinically meaningful analgesic effects. Drug-related adverse events were similar to those for oral gabapentin.
Magnesium Sulfate
Magnesium has analgesic properties, primarily related to the regulation of calcium influx into cells134 and antagonism of NMDA receptors in the CNS.135–137 Several small trials investigating the analgesic efficacy of perioperative intravenous magnesium have been published, with conflicting results.138–140 However, a meta-analysis of all available trials of systemically administered magnesium reported a reduction in postoperative opioid requirements approximately equal to that of ketorolac.141 Animal studies have reported histologic neurotoxicity with weight-adjusted doses similar to those used in most human clinical trials to date,142 whereas two case reports have described patients suffering from disorientation143 and continuous periumbilical burning pain144 following the injection of neuraxial magnesium.
An animal model showed that direct intrathecal administration of magnesium enhanced the antinociceptive effect of opioids for acute incisional pain145 and suppressed nociceptive responses in neuropathic pain models.146 The earliest clinical trials investigating intrathecal and epidural magnesium reported an increase in the median duration of analgesia147 and decrease in opioid consumption by 25%,148respectively. The dose of neuraxial magnesium that confers optimal analgesia with the fewest possible side effects remains unclear.
The analgesic efficacy and safety of neuraxial magnesium for postoperative pain management has been assessed in a meta-analysis.149 Intrathecal magnesium increased the time to first analgesic request, reduced morphine consumption at 24 hours postoperatively, and modestly reduced early postoperative pain scores. When administered in the epidural space, magnesium also increased the time to first analgesic request. These acute pain–related benefits reportedly occur without increased risk of hypotension, bradycardia, or sedation. The lack of reported complications associated with neuraxial magnesium must not be interpreted as an endorsement of its safety. Several animal studies have demonstrated that a risk of clinically relevant neurologic injury does exist.150,151
Conclusion
Neuraxial drug administration via the intrathecal and epidural route remains an important treatment option for the provision of anesthesia as well as analgesia in acute, cancer, and chronic pain. Additional dose-effect studies are needed for most agents to strengthen our understanding of the safety profile of these drugs when administered neuraxially before they become a part of routine clinical practice.
References
1. Walker SM, Goudas LC, Cousins MJ, et al. Combination spinal analgesic chemotherapy: a systematic review. Anesth Analg. 2002;95(3):674–715.
2. Coote JH. Noradrenergic projections to the spinal cord and their role in cardiovascular control. J Auton Nerv Syst. 1985;14(3):255–262.
3. Naguib M, Yaksh TL. Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with mu and alpha 2 receptor systems. Anesthesiology. 1994;80(6):1338–1348.
4. Dobrydnjov I, Axelsson K, Gupta A, et al. Improved analgesia with clonidine when added to local anesthetic during combined spinal-epidural anesthesia for hip arthroplasty: a double-blind, randomized and placebo-controlled study. Acta Anaesthesiol Scand. 2005;49(4):538–545.
5. Huang YS, Lin LC, Huh BK, et al. Epidural clonidine for postoperative pain after total knee arthroplasty: a dose-response study. Anesth Analg. 2007;104(5):1230–1235.
6. Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain. The Epidural Clonidine Study Group. Pain. 1995;61(3):391–399.
7. Kanazi GE, Aouad MT, Jabbour-Khoury SI, et al. Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesthesiol Scand. 2006;50(2):222–227.
8. Eisenach JC, De Kock M, Klimscha W. alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984–1995). Anesthesiology. 1996;85(3):655–674.
9. De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia and long-term antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery. Anesth Analg. 2005;101(2):566–572, table of contents.
10. Eisenach JC, Hood DD, Curry R. Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg. 1998;87(3):591–596.
11. Lavand’homme PM, Roelants F, Waterloos H, et al. An evaluation of the postoperative antihyperalgesic and analgesic effects of intrathecal clonidine administered during elective cesarean delivery. Anesth Analg. 2008;107(3):948–955.
12. Brennan TJ, Kehlet H. Preventive analgesia to reduce wound hyperalgesia and persistent postsurgical pain: not an easy path. Anesthesiology. 2005;103(4):681–683.
13. Elia N, Culebras X, Mazza C, et al. Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials. Reg Anesth Pain Med. 2008;33(2):159–167.
14. Eisenach JC, Shafer SL, Bucklin BA, et al. Pharmacokinetics and pharmacodynamics of intraspinal dexmedetomidine in sheep. Anesthesiology. 1994;80(6):1349–1359.
15. Fisher B, Zornow MH, Yaksh TL, et al. Antinociceptive properties of intrathecal dexmedetomidine in rats. Eur J Pharmacol. 1991;192(2):221–225.
16. Ishii H, Kohno T, Yamakura T, et al. Action of dexmedetomidine on the substantia gelatinosa neurons of the rat spinal cord. Eur J Neurosci. 2008;27(12):3182–3190.
17. Schnaider TB, Vieira AM, Brandao AC, et al. Intraoperative analgesic effect of epidural ketamine, clonidine or dexmedetomidine for upper abdominal surgery [in Portuguese]. Rev Bras Anestesiol. 2005;55(5):525–531.
18. Saadawy I, Boker A, Elshahawy MA, et al. Effect of dexmedetomidine on the characteristics of bupivacaine in a caudal block in pediatrics. Acta Anaesthesiol Scand. 2009;53(2):251–256.
19. Al-Mustafa MM, Abu-Halaweh SA, Aloweidi AS, et al. Effect of dexmedetomidine added to spinal bupivacaine for urological procedures. Saudi Med J. 2009;30(3):365–370.
20. Elhakim M, Abdelhamid D, Abdelfattach H, et al. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703–709.
21. Hanoura S, Hassanin R, Singh R. Intraoperative conditions and quality of postoperative analgesia after adding dexmedetomidine to epidural bupivacaine and fentanyl in elective cesarean section using combined spinal-epidural anesthesia. Anesth Essays Res. 2013;7:168–172.
22. El-Hennawy AM, Abd-Elwahab AM, Abd-Elmaksoud AM, et al. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. Br J Anaesth. 2009;103(2):268–274.
23. Emery E. Intrathecal baclofen. Literature review of the results and complications [in French]. Neurochirurgie. 2003;49(2–3, pt 2):276–288.
24. Grewal A. Dexmedetomidine: new avenues. J Anaesthesiol Clin Pharmacol. 2011;27(3):297–302.
25. Naguib M, Yaksh TL. Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord. Anesth Analg. 1997;85(4):847–853.
26. Congedo E, Sgreccia M, De Cosmo G. New drugs for epidural analgesia. Curr Drug Targets. 2009;10(8):696–706.
27. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology. 1995;82(2):331–343.
28. Krukowski JA, Hood DD, Eisenach JC, et al. Intrathecal neostigmine for post-cesarean section analgesia: dose response. Anesth Analg. 1997;84(6):1269–1275.
29. Nelson KE, D’Angelo R, Foss ML, et al. Intrathecal neostigmine and sufentanil for early labor analgesia. Anesthesiology. 1999;91(5):1293–1298.
30. Lauretti GR, de Oliveira R, Reis MP, et al. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology. 1999;90(6):1534–1538.
31. Omais M, Lauretti GR, Paccola CA. Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery. Anesth Analg. 2002;95(6):1698–1701, table of contents.
32. Roelants F, Lavand’homme PM. Epidural neostigmine combined with sufentanil provides balanced and selective analgesia in early labor. Anesthesiology. 2004;101(2):439–444.
33. Roelants F, Lavand’homme PM, Mercier-Fuzier V. Epidural administration of neostigmine and clonidine to induce labor analgesia: evaluation of efficacy and local anesthetic-sparing effect. Anesthesiology. 2005;102(6):1205–1210.
34. Roelants F, Rizzo M, Lavand’homme P. The effect of epidural neostigmine combined with ropivacaine and sufentanil on neuraxial analgesia during labor. Anesth Analg. 2003;96(4):1161–1166, table of contents.
35. Harjai M, Chandra G, Bhatia VK, et al. A comparative study of two different doses of epidural neostigmine coadministered with lignocaine for post operative analgesia and sedation. J Anaesthesiol Clin Pharmacol. 2010;26(4):461–464.
36. Ho KM, Ismail H, Lee KC, et al. Use of intrathecal neostigmine as an adjunct to other spinal medications in perioperative and peripartum analgesia: a meta-analysis. Anaesth Intensive Care. 2005;33(1):41–53.
37. Kirdemir P, Ozkocak I, Demir T, et al. Comparison of postoperative analgesic effects of preemptively used epidural ketamine and neostigmine. J Clin Anesth. 2000;12(7):543–548.
38. Marucio RL, Luna SP, Neto FJ, et al. Postoperative analgesic effects of epidural administration of neostigmine alone or in combination with morphine in ovariohysterectomized dogs. Am J Vet Res. 2008;69(7):854–860.
39. Batra YK, Rajeev S, Panda NB, et al. Intrathecal neostigmine with bupivacaine for infants undergoing lower abdominal and urogenital procedures: dose response. Acta Anaesthesiol Scand. 2009;53(4):470–475.
40. Gabopoulou Z, Vadalouca A, Velmachou K, et al. Epidural calcitonin: does it provide better postoperative analgesia? An analysis of the haemodynamic, endocrine, and nociceptive responses of salmon calcitonin and opioids in epidural anesthesia for hip arthroplasty surgery. Pain Pract. 2002;2(4):326–331.
41. Kathirvel S, Sadhasivam S, Saxena A, et al. Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia. 2000;55(9):899–904.
42. Brock-Utne JG, Kallichurum S, Mankowitz E, et al. Intrathecal ketamine with preservative histological effects on spinal nerve roots of baboons. S Afr Med J. 1982;61(12):440–441.
43. Borgbjerg FM, Svensson BA, Frigast C, et al. Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and electron microscopic examination. Anesth Analg. 1994;79(1):105–111.
44. Errando CL, Sifre C, Moliner S, et al. Subarachnoid ketamine in swine—pathological findings after repeated doses: acute toxicity study. Reg Anesth Pain Med. 1999;24(2):146–152.
45. Rojas AC, Alves JG, Moreira ELR, et al. The effects of subarachnoid administration of preservative-free S(+)-ketamine on spinal cord and meninges in dogs. Anesth Analg. 2012;114(2):450–455.
46. Naguib M, Adu-Gyamfi Y, Absood GH, et al. Epidural ketamine for postoperative analgesia. Can Anaesth Soc J. 1986;33(1):16–21.
47. Kawana Y, Sato H, Shimada H, et al. Epidural ketamine for postoperative pain relief after gynecologic operations: a double-blind study and comparison with epidural morphine. Anesth Analg. 1987;66(8):735–738.
48. Locatelli BG, Frawley G, Spotti A, et al. Analgesic effectiveness of caudal levobupivacaine and ketamine. Br J Anaesth. 2008;100(5):701–706.
49. Yang CY, Wong CS, Chang JY, et al. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth. 1996;43(4):379–383.
50. Feltracco P, Barbieri S, Rizzi S, et al. Brief report: perioperative analgesic efficacy and plasma concentrations of S+ ketamine in continuous epidural infusion during thoracic surgery. Anesth Analg. 2013;116(6):1371–1375.
51. Naguib M, Sharif AM, Seraj M, et al. Ketamine for caudal analgesia in children: comparison with caudal bupivacaine. Br J Anaesth. 1991;67(5):559–564.
52. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004;99(2):482–495, table of contents.
53. Bion JF. Intrathecal ketamine for war surgery. A preliminary study under field conditions. Anaesthesia. 1984;39(10):1023–1028.
54. Karpinski N, Dunn J, Hansen L, et al. Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain. 1997;73(1):103–105.
55. Ho KM, Ismail H. Use of intrathecal midazolam to improve perioperative analgesia: a meta-analysis. Anaesth Intensive Care. 2008;36(3):365–373.
56. Goodchild CS, Guo Z, Musgreave A, et al. Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors. Br J Anaesth. 1996;77(6):758–763.
57. Naguib M, el Gammal M, Elhattab YS, et al. Midazolam for caudal analgesia in children: comparison with caudal bupivacaine. Can J Anaesth. 1995;42(9):758–764.
58. Chakraborty S, Chakrabarti J, Bhattacharya D. Intrathecal tramadol added to bupivacaine as spinal anesthetic increases analgesic effect of the spinal blockade after major gynecological surgeries. Indian J Pharmacol. 2008;40(4):180–182.
59. Kumar P, Rudra A, Pan AK, et al. Caudal additives in pediatrics: a comparison among midazolam, ketamine, and neostigmine coadministered with bupivacaine. Anesth Analg. 2005;101(1):69–73, table of contents.
60. Nishiyama T, Matsukawa T, Hanaoka K. Continuous epidural administration of midazolam and bupivacaine for postoperative analgesia. Acta Anaesthesiol Scand. 1999;43(5):568–572.
61. Nishiyama T, Matsukawa T, Hanaoka K. Effects of adding midazolam on the postoperative epidural analgesia with two different doses of bupivacaine. J Clin Anesth. 2002;14(2):92–97.
62. Canavero S, Bonicalzi V, Clemente M. No neurotoxicity from long-term (>5 years) intrathecal infusion of midazolam in humans. J Pain Symptom Manage. 2006;32(1):1–3.
63. Hodgson PS, Neal JM, Pollock JE, et al. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg. 1999;88(4):797–809.
64. Tucker AP, Lai C, Nadeson R, et al. Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg. 2004;98(6):1512–1520, table of contents.
65. Tucker AP, Mezzatesta J, Nadeson R, et al. Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain. Anesth Analg. 2004;98(6):1521–1527, table of contents.
66. Yanez A, Peleteiro R, Camba MA. Intrathecal administration of morphine, midazolam, and their combination in 4 patients with chronic pain [in Spanish]. Rev Esp Anestesiol Reanim. 1992;39(1):40–42.
67. Johansen MJ, Gradert TL, Satterfield WC, et al. Safety of continuous intrathecal midazolam infusion in the sheep model. Anesth Analg. 2004;98(6):1528–1535.
68. Reid M, Herrera-Marschitz M, Hokfelt T, et al. Differential modulation of striatal dopamine release by intranigral injection of gamma-aminobutyric acid (GABA), dynorphin A and substance P. Eur J Pharmacol. 1988;147(3):411–420.
69. Splinter WM, MacNeill HB, Menard EA, et al. Midazolam reduces vomiting after tonsillectomy in children. Can J Anaesth. 1995;42(3):201–203.
70. Kohno T, Wakai A, Ataka T, et al. Actions of midazolam on excitatory transmission in dorsal horn neurons of adult rat spinal cord. Anesthesiology. 2006;104(2):338–343.
71. Yanez A, Sabbe MB, Stevens CW, et al. Interaction of midazolam and morphine in the spinal cord of the rat. Neuropharmacology. 1990;29(4):359–364.
72. Kim MH, Lee YM. Intrathecal midazolam increases the analgesic effects of spinal blockade with bupivacaine in patients undergoing haemorrhoidectomy. Br J Anaesth. 2001;86(1):77–79.
73. Boussofara M, Carles M, Raucoules-Aime M, et al. Effects of intrathecal midazolam on postoperative analgesia when added to a bupivacaine-clonidine mixture. Reg Anesth Pain Med. 2006;31(6):501–505.
74. Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg. 2004;98(6):1536–1545, table of contents.
75. Cousins MJ, Miller RD. Intrathecal midazolam: an ethical editorial dilemma. Anesth Analg. 2004;98(6):1507–1508.
76. Yaksh TL, Allen JW. Preclinical insights into the implementation of intrathecal midazolam: a cautionary tale. Anesth Analg. 2004;98(6):1509–1511.
77. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther. 1992;260(1):275–285.
78. Baraka A, Jabbour S, Ghabash M, et al. A comparison of epidural tramadol and epidural morphine for postoperative analgesia. Can J Anaesth. 1993;40(4):308–313.
79. Delilkan AE, Vijayan R. Epidural tramadol for postoperative pain relief. Anaesthesia. 1993;48(4):328–331.
80. Fu YP, Chan KH, Lee TK, et al. Epidural tramadol for postoperative pain relief. Ma Zui Xue Za Zhi. 1991;29(3):648–652.
81. Pan AK, Mukherjee P, Rudra A. Role of epidural tramadol hydrochloride on postoperative pain relief in caesarean section delivery. J Indian Med Assoc. 1997;95(4):105–106.
82. Grace D, Fee JP. Ineffective analgesia after extradural tramadol hydrochloride in patients undergoing total knee replacement. Anaesthesia. 1995;50(6):555–558.
83. Wilder-Smith CH, Wilder-Smith OH, Farschtschian M, et al. Preoperative adjuvant epidural tramadol: the effect of different doses on postoperative analgesia and pain processing. Acta Anaesthesiol Scand. 1998;42(3):299–305.
84. Alhashemi JA, Kaki AM. Effect of intrathecal tramadol administration on postoperative pain after transurethral resection of prostate. Br J Anaesth. 2003;91(4):536–540.
85. Frikha N, Ellachtar M, Mebazaa MS, et al. Combined spinal-epidural analgesia in labor—comparison of sufentanil vs tramadol. Middle East J Anesthesiol. 2007;19(1):87–96.
86. Subedi A, Biswas BK, Tripathi M, et al. Analgesic effects of intrathecal tramadol in patients undergoing caesarean section: a randomised, double-blind study. Int J Obstet Anesth. 2013;22(4):316–321.
87. Ozcengiz D, Gunduz M, Ozbek H, et al. Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy. Paediatr Anaesth. 2001;11(4):459–464.
88. Lee IH, Lee IO. The antipruritic and antiemetic effects of epidural droperidol: a study of three methods of administration. Anesth Analg. 2007;105(1):251–255.
89. Ahmad-Sabry MH, Shareghi G. Long-term use of intrathecal droperidol as an excellent antiemetic in nonmalignant pain—a retrospective study. Middle East J Anesthesiol. 2012;21(6):857–862.
90. Grip G, Svensson BA, Gordh T Jr, et al. Histopathology and evaluation of potentiation of morphine-induced antinociception by intrathecal droperidol in the rat. Acta Anaesthesiol Scand. 1992;36(2):145–152.
91. Poon A, Sawynok J. Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. Pain. 1998;74(2–3):235–245.
92. Gomes JA, Li X, Pan HL, et al. Intrathecal adenosine interacts with a spinal noradrenergic system to produce antinociception in nerve-injured rats. Anesthesiology. 1999;91(4):1072–1079.
93. Eisenach JC, Hood DD, Curry R. Phase I safety assessment of intrathecal injection of an American formulation of adenosine in humans. Anesthesiology. 2002;96(1):24–28.
94. Rane K, Segerdahl M, Goiny M, et al. Intrathecal adenosine administration: a phase 1 clinical safety study in healthy volunteers, with additional evaluation of its influence on sensory thresholds and experimental pain. Anesthesiology. 1998;89(5):1108–1115; discussion 9A.
95. Karlsten R, Gordh T Jr. An A1-selective adenosine agonist abolishes allodynia elicited by vibration and touch after intrathecal injection. Anesth Analg. 1995;80(4):844–847.
96. Eisenach JC, Curry R, Hood DD. Dose response of intrathecal adenosine in experimental pain and allodynia. Anesthesiology. 2002;97(4):938–942.
97. Rane K, Sollevi A, Segerdahl M. Intrathecal adenosine administration in abdominal hysterectomy lacks analgesic effect. Acta Anaesthesiol Scand. 2000;44(7):868–872.
98. Rane K, Sollevi A, Segerdahl M. A randomised double-blind evaluation of adenosine as adjunct to sufentanil in spinal labour analgesia. Acta Anaesthesiol Scand. 2003;47(5):601–603.
99. Eisenach JC, Hood DD, Curry R. Preliminary efficacy assessment of intrathecal injection of an American formulation of adenosine in humans. Anesthesiology. 2002;96(1):29–34.
100. Schug SA, Buerkle H, Moharib M, et al. New drugs for neuraxial blockade. Curr Opin Anaesthesiol. 1999;12(5):551–557.
101. Yaksh TL, Horais KA, Tozier N, et al. Intrathecal ketorolac in dogs and rats. Toxicol Sci. 2004;80(2):322–334.
102. McGivern JG. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007;3(1):69–85.
103. Schmidtko A, Lotsch J, Freynhagen R, et al. Ziconotide for treatment of severe chronic pain. Lancet. 2010;375(9725):1569–1577.
104. Wermeling DP. Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain. Pharmacotherapy. 2005;25(8):1084–1094.
105. Bowersox SS, Gadbois T, Singh T, et al. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. J Pharmacol Exp Ther. 1996;279(3):1243–1249.
106. Brose WG, Gutlove DP, Luther RR, et al. Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain. Clin J Pain. 1997;13(3):256–259.
107. Penn RD, Paice JA. Adverse effects associated with the intrathecal administration of ziconotide. Pain. 2000;85(1–2):291–296.
108. Atanassoff PG, Hartmannsgruber MW, Thrasher J, et al. Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med. 2000;25(3):274–278.
109. Wermeling D, Drass M, Ellis D, et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol. 2003;43(6):624–636.
110. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31(5):393–406.
111. National Institutes of Health Clinical Center. Resiniferatoxin to to treat severe pain associated with advanced cancer. http://clinical trials.gov/ct2/show/study/NCT00804154. Accessed April 1, 2014.
112. Kern SE, Allen J, Wagstaff J, et al. The pharmacokinetics of the conopeptide contulakin-G (CGX-1160) after intrathecal administration: an analysis of data from studies in beagles. Anesth Analg. 2007;104(6):1514–1520, table of contents.
113. Penn RD, Paice JA, Kroin JS. Intrathecal octreotide for cancer pain. Lancet. 1990;335(8691):738.
114. Penn RD, Paice JA, Kroin JS. Octreotide: a potent new non-opiate analgesic for intrathecal infusion. Pain. 1992;49(1):13–19.
115. Paice JA, Penn RD, Kroin JS. Intrathecal octreotide for relief of intractable nonmalignant pain: 5-year experience with two cases. Neurosurgery. 1996;38(1):203–207.
116. Deer TR, Kim CK, Bowman RG II, et al. The use of continuous intrathecal infusion of octreotide in patients with chronic pain of noncancer origin: an evaluation of side-effects and toxicity in a prospective double-blind fashion. Neuromodulation. 2005;8(3):171–175.
117. Slonimski M, Abram SE, Zuniga RE. Intrathecal baclofen in pain management. Reg Anesth Pain Med. 2004;29(3):269–276.
118. Vatine J, Magora F, Shochina M, et al. Effect of intrathecal baclofen in low back pain with root compression symptoms. Pain Clin. 1989;2:207–217.
119. Hsieh JC, Penn RD. Intrathecal baclofen in the treatment of adult spasticity. Neurosurg Focus. 2006;21(2):e5.
120. Herman RM, D’Luzansky SC, Ippolito R. Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain. 1992;8(4):338–345.
121. Loubser PG, Akman NM. Effects of intrathecal baclofen on chronic spinal cord injury pain. J Pain Symptom Manage. 1996;12(4):241–247.
122. Sanders JC, Gerstein N, Torgeson E, et al. Intrathecal baclofen for postoperative analgesia after total knee arthroplasty. J Clin Anesth. 2009;21(7):486–492.
123. Broseta J, Garcia-March G, Sanchez-Ledesma MJ, et al. Chronic intrathecal baclofen administration in severe spasticity. Stereotact Funct Neurosurg. 1990;54–55:147–153.
124. Ochs GA. Intrathecal baclofen. Baillieres Clin Neurol. 1993;2(1):73–86.
125. Donner B, Tryba M, Zenz M, et al. Intrathecal and epidural administration of non-opioid analgesics in acute and chronic pain treatment [in German]. Schmerz. 1994;8(2):71–81.
126. Rastogi V, dutta R, Kumar GP. A comparative study of premedication for prevention of vomiting induced by intrathecal calcitonin: a double blind study. Internet J Anaesth. 2008;16(2):3.
127. Eisenach JC, Curry R, Rauck R, et al. Role of spinal cyclooxygenase in human postoperative and chronic pain. Anesthesiology. 2010;112(5):1225–1233.
128. Eisenach JC, Curry R, Tong C, et al. Effects of intrathecal ketorolac on human experimental pain. Anesthesiology. 2010;112(5):1216–1224.
129. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science. 1992;257(5074):1276–1279.
130. Pellerin M, Hardy F, Abergel A, et al. Chronic refractory pain in cancer patients. Value of the spinal injection of lysine acetylsalicylate. 60 cases [in French]. Presse Med. 1987;16(30):1465–1468.
131. Eisenach JC, Curry R, Hood DD, et al. Phase I safety assessment of intrathecal ketorolac. Pain. 2002;99(3):599–604.
132. Morello CM, Leckband SG, Stoner CP, et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999;159(16):1931–1937.
133. Steinman MA, Bero LA, Chren MM, et al. Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Ann Intern Med. 2006;145(4):284–293.
134. Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Heart J. 1984;108(1):188–193.
135. Feria M, Abad F, Sanchez A, et al. Magnesium sulphate injected subcutaneously suppresses autotomy in peripherally deafferented rats. Pain. 1993;53(3):287–293.
136. Tramer MR, Schneider J, Marti RA, et al. Role of magnesium sulfate in postoperative analgesia. Anesthesiology. 1996;84(2):340–347.
137. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44(3):293–299.
138. Jaoua H, Zghidi SM, Wissem L, et al. Effectiveness of intravenous magnesium on postoperative pain after abdominal surgery versus placebo: double blind randomized controlled trial [in French]. Tunis Med. 2010;88(5):317–323.
139. Tramer MR, Glynn CJ. An evaluation of a single dose of magnesium to supplement analgesia after ambulatory surgery: randomized controlled trial. Anesth Analg. 2007;104(6):1374–1379, table of contents.
140. Zarauza R, Saez-Fernandez AN, Iribarren MJ, et al. A comparative study with oral nifedipine, intravenous nimodipine, and magnesium sulfate in postoperative analgesia. Anesth Analg. 2000;91(4):938–943.
141. De Oliveira G, Castro-Alves L, Khan J, et al. Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2013;119(1):178–190.
142. Saeki H, Matsumoto M, Kaneko S, et al. Is intrathecal magnesium sulfate safe and protective against ischemic spinal cord injury in rabbits? Anesth Analg. 2004;99(6):1805–1812, table of contents.
143. Goodman EJ, Haas AJ, Kantor GS. Inadvertent administration of magnesium sulfate through the epidural catheter: report and analysis of a drug error. Int J Obstet Anesth. 2006;15(1):63–67.
144. Dror A, Henriksen E. Accidental epidural magnesium sulfate injection. Anesth Analg. 1987;66(10):1020–1021.
145. Kroin JS, McCarthy RJ, Von Roenn N, et al. Magnesium sulfate potentiates morphine antinociception at the spinal level. Anesth Analg. 2000;90(4):913–917.
146. Xiao WH, Bennett GJ. Magnesium suppresses neuropathic pain responses in rats via a spinal site of action. Brain Res. 1994;666(2):168–172.
147. Buvanendran A, McCarthy RJ, Kroin JS, et al. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg. 2002;95(3):661–666, table of contents.
148. Bilir A, Gulec S, Erkan A, et al. Epidural magnesium reduces postoperative analgesic requirement. Br J Anaesth. 2007;98(4):519–523.
149. Albrecht E, Kirkham KR, Liu SS, et al. The analgesic efficacy and safety of neuraxial magnesium sulphate: a quantitative review. Anaesthesia. 2013;68(2):190–202.
150. Chanimov M, Cohen ML, Grinspun Y, et al. Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate. An experimental study in a rat model. Anaesthesia. 1997;52(3):223–228.
151. Simpson JI, Eide TR, Schiff GA, et al. Intrathecal magnesium sulfate protects the spinal cord from ischemic injury during thoracic aortic cross-clamping. Anesthesiology. 1994;81(6):1493–1499; discussion 26A–27A.