Intraspinal Therapy for the Treatment of Chronic Pain: A Review of the Literature Between 1990 and 2005 and Suggested Protocol for Its Rational and Safe Use

The administration of intrathecal drugs has been shown to be efficacious in the treatment of both cancer pain and noncancer pain in patients who do not respond well to conventional treatment, in those who are unable to tolerate side‐effects of opioids, and in those who constantly require significant increases in drug dosing. Although morphine represents the “drug of choice” for intrathecal administration, the use of alternative drugs (e.g., bupivacaine, clonidine, and hydromorphone) appears promising for intrathecal therapy of pain in patients who are unresponsive to morphine, those who cannot tolerate its side‐effects, and those patients with neuropathic pain. This study analyzes results of studies published from 1990 to 2005 in order to evaluate the efficacy of intraspinal therapy.     

Alternative Intrathecal Agents for the Treatment of Pain

There is a need to develop alternative agents for intrathecal pain therapy for patients who either cannot tolerate the side effects of or who no longer obtain sufficient analgesia with opioids. The experimental use of several compounds in intrathecal drug delivery is currently in progress, with the development of clonidine as the single most important advance in the improvement of pain treatment. Clonidine, an α₂-adrenergic receptor agonist, appears to be safe and effective in the treatment of cancer and nonmalignant pain, with its effects most pronounced in patients whose pain consists of a neuropathic component. Other possible effective agents for intrathecal delivery include bupivacaine, octreotide, and SNX-111. The preclinical and clinical profiles for these promising new intrathecal pain medications are discussed.     

Acute Exacerbation of Hereditary Coproporphyria Mimics Early Surgical Infection Following Intrathecal Pump Implantation for Chronic Abdominal Pain: A Case Report

Objective: Pain physicians should also be aware of rare complications that can occur after intrathecal pump (ITP) placement. One such rare complication includes an acute exacerbation of hereditary coproporphyria (HCP). Methods: We present a case report that illustrates how an acute exacerbation of HCP can mimic an early surgical post‐procedure infection after ITP implantation. Results: The patient's rapid onset of symptoms two hours after the procedure keyed into HCP as the underlying cause, as acute wound infections rarely occur in the several hours following surgery. After symptomatic treatment of her HCP acute exacerbation, the patient clinically improved without the development of further symptoms or adverse sequelae. She reported considerable pain relief with the implanted drug delivery system. Conclusion: In a setting with multiple confounders, a methodical history and physical examination, close monitoring, and a comprehensive understanding of potential complications can prevent unnecessary ITP extraction and streamline the delivery of appropriate care.     

Intrathecal inflammatory masses: is the yearly opioid dose increase an early indicator?

Objectives: The objective of this study is to investigate the association between intrathecal drug, flow rate, drug concentration, and drug dose with the formation of intrathecal inflammatory masses. Methods: A retrospective longitudinal study of 56 consecutive patients receiving long‐term intrathecal analgesic administration was undertaken through screening of medical records. Data regarding drug flow rate, dose per day, and concentration of drugs administered were recorded for morphine, diamorphine, bupivicaine, clonidine and baclofen and averages computed. Results: The average follow‐up time post‐implant was 91 ± 55 months (range: 9–209). Four of the 56 patients were diagnosed with intrathecal granuloma indicating a rate of 7%, the equivalent to 0.009 events per patient year. Twenty‐one of the patients had received morphine either alone or combined; 22 had received diamorphine either alone or mixed; and 13 crossed over from morphine to diamorphine or the inverse. None of the patients with granuloma crossed over before diagnosis. A significant correlation was found between opioid dose (r= 0.275, p < 0.05), yearly increase of the opioid dose (r= 0.433, p < 0.05), and granuloma formation. Clonidine appeared to have a protective effect for the non‐granuloma patients. No association was found with flow rate (r= 0.056) or opioid concentration (r= 0.214). Conclusion: This is the first detailed study showing an association of diamorphine with granulomas. This study supports the previous finding of intrathecal opioid dose being a risk factor for intrathecal granulomas and clonidine being protective. In addition we have found that the yearly increase in opioid dose is a risk factor for granulomas and could serve as an indicator for closer surveillance.     

The Management of Pain From Collapse of Osteoporotic Vertebrae With Continuous Intrathecal Morphine Infusion

Objectives. Vertebral fractures are the most common consequences of severe osteoporosis. The chronic pain from collapse of osteoporotic vertebrae affects quality of life (QoL) and autonomy of patients. The management of pain with oral or transdermal opiates can cause severe side‐effects. Continuous intrathecal administration of morphine through an implantable pump might represent an alternative therapy to conventional oral or transdermal administration of opioids and has some advantages and disadvantages for pain relief and improvement in QoL when compared to conventional opioid delivery. It is our objective to report our experience using intrathecal delivery of analgesics in a population of patients with refractory pain due to vertebral fractures. Materials and Methods. In 24 patients, refractory to conventional delivery of opioids, we used intrathecal analgesic therapy. To test for efficacy and improvement in QoL, we administered the visual analog scale (VAS) for pain and the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Before patients were selected for pump implantation, an intraspinal drug delivery trial was performed to monitor side‐effects and responses to intrathecal therapy. Results. Significant pain relief was obtained in all implanted patients. Using the QUALEFFO, we observed significant improvement of all variables such as QDL (quality of daily life), DW (domestic work), ambulation, and PHS (perception of health status), before and after one year after pump implantation. With intrathecal morphine infusion, none of the 24 patients required additional systemic analgesic medication. The mean morphine dose during the spinal trial was 11.28 mg/day, 7.92 mg/day at pump implantation, and 16.32 mg/day at one‐year follow‐up. Conclusions. Our results show that intrathecal administration of morphine efficiently relieves the symptoms of pain and improves QoL. Continuous intrathecal administration of morphine appears to be an alternative therapy to conventional analgesic drug delivery and has advantages in those patients who have severe side‐effects with systemic administration of analgesics.     

Stability and Analgesic Efficacy of Di‐acetyl Morphine (Diamorphine) Compared with Morphine in Implanted Intrathecal Pumps In Vivo

The objective of this study was to investigate di‐acetyl morphine as an alternative opioid analgesic for use in implanted intrathecal drug delivery systems because of its greater solubility through evaluation of its stability in vivo and analgesic efficacy in the period between pump refills. Contents of intrathecal drug delivery system reservoirs (SynchroMed, Medtronic, Inc., Minneapolis, MN) that had been filled with di‐acetyl morphine dissolved in saline (21), bupivacaine (9), or in both bupivacaine and clonidine (19) were sampled in vivo between 1 and 125 days after refill. The samples were assayed for di‐acetyl morphine and its breakdown products by micellar electrokinetic capillary chromatography. Prospective daily numerical pain scores between pump refills, using 11‐point Likert scales, on 24 patients with implanted SynchroMed pumps (12 delivering di‐acetyl morphine in saline, 12 were delivering morphine in saline) were collected. Results showed that di‐acetyl morphine immediately started to decay to mono‐acetyl morphine in implanted Synchromed pumps with half‐life of 50 days. Mono‐acetyl morphine decayed to morphine with a maxima estimated at 125 days. There was no clinically significant change in average weekly pain scores for up to ten weeks in either group (range, 2.5 to 2.8 for diamorphine and 2.7 to 3.1 for morphine) (2‐way repeated ANOVA, F(9,220) = 0.98, n.s.). We conclude that di‐acetyl morphine and its breakdown products, 6 mono‐acetyl morphine and morphine, provide similar analgesia to morphine alone when administered by intrathecal pump for a period of at least ten weeks and may be a useful alternative when a more soluble agent is favored.     

Perceived Success and Failure of Intrathecal Infusion Pump Implantation in Chronic Pain Patients

Objectives. Over the past few years, there has been an increased reliance on the intrathecal delivery of drugs for patients suffering from intractable pain. We sought to demonstrate the effectiveness of the intrathecal pain pump by examining self‐reported pre‐ and postimplantation pain levels. Methods. Eighty‐four patients who had elected to implant a Medtronic SynchroMed 1 or 2 system in order to control their pain were asked to complete a survey. The survey consisted of pain ratings before implantation, pain ratings postimplantation, medications used before and after implantation, and patient satisfaction with the procedure. Results. Perceived success rate for implantation is 68%, when measured by the ability to reduce reliance on oral medication. When measured by willingness to undergo the procedure again, the success rate is 86%. Conclusions. Overall, the implantation of an intrathecal pain pump is an effective way for most people to manage their intractable pain and reduce reliance on oral medications.     

Antinociceptive interactions between intrathecally administered alpha noradrenergic agonists and 5'-N-ethylcarboxamide adenosine

Recently, it has been shown that intrathecal injection of norepinephrine and the mixed A1/A2 adenosine agonist 5'-N-ethylcarboxamide adenosine (NECA) interact in a supra-additive manner to produce antinociception. The present studies were designed to determine whether alpha 1 or alpha 2 noradrenergic receptors are involved in producing the antinociception induced by NECA and norepinephrine. The results indicated that intrathecal injection of NECA (0.97-4.9 nmol), the alpha 2 noradrenergic agonist clonidine (3.8-375 nmol), or the alpha 1 agonist phenylephrine (4.9-73.4 nmol) produced dose-dependent antinociception in rats. Furthermore, intrathecal injection of subeffective doses of NECA and clonidine interacted supra-additively to produce potent antinociception. In contrast, no supra-additive interaction was observed between NECA and phenylephrine. The supra-additive interaction of NECA and clonidine did not appear to result from alterations in cardiovascular tone because changes in blood pressure and nociceptive thresholds were not correlated in time. These results suggest that the noradrenergic component of the supra-additive interaction between adenosine A2 receptor agonists and noradrenergic agonists is mediated by alpha 2 noradrenergic receptors.     

Bilateral Subdural Hematoma Following Implantation of Intrathecal Drug Delivery Device

Objectives: To report a case of bilateral subacute subdural hematoma following implantation of intrathecal drug delivery device. Materials and Methods: We present here the case of a 41‐year‐old woman with multiple sclerosis and intractable spasticity who developed a bilateral subacute subdural hematoma after the placement of an intrathecal catheter connected to a programmable pump for baclofen infusion. Results: Surgical drainage of the hematoma resulted in full neurologic recovery. This complication due to intracranial hypotension following lumbar puncture has been previously reported only once in patients with implanted intrathecal drug delivery device. Conclusions: Medical and nursing staff dealing with intrathecal therapy should be aware of this potentially severe complication.     

Effect of continuous systemic infusion of D-amphetamine on the sensitivity of nigral dopamine cells to apomorphine inhibition of firing rates

Intrathecally-administered clonidine inhibited the spontaneous firing of single neurons in the pontine nucleus locus coeruleus of rats. Such inhibition of neuron firing was not observed when the non-lipophilic alpha 2 adrenoceptor agonist (oxymetazoline) was administered intrathecally. It is concluded that lipophilic drugs like clonidine, when administered intrathecally, can have profound supraspinal actions and thus caution should be exercised in interpreting the sites of action of such drugs.     

Spinalization unmasks clonidine's alpha 1-adrenergic mediated excitation of the flexor reflex in rats

Clonidine exerts alpha 2-adrenergic mediated depressant effects on most behaviors measured in a normal animal. However, in the spinal-transected (spinalized) animal, clonidine apparently facilitates the flexor reflex through a stimulation of spinal alpha 1-adrenoceptors. The purpose of the present study was to determine if spinalization per se causes the shift in clonidine's profile from an alpha 2- to an alpha 1-adrenergic agonist. The hindlimb flexor reflex was elicited by electrical pulses delivered through electrodes implanted subcutaneously in the hindpaw and was measured with a force transducer and polygraph. In contrast to an alpha 2-adrenergic mediated inhibition of the flexor reflex in intact rats, clonidine produced an alpha 1-adrenergic mediated increase in flexor reflex amplitude in spinalized rats. Because decerebration did not alter the depression due to clonidine, and intraventricular (but not intrathecal) administration of oxymetazoline mimicked the effect of clonidine, the depressant effects of alpha 2-adrenergic agonists are mediated through alpha 2-adrenergic receptors localized in the brainstem. Alternate methods for inducing a functional spinal transection (spinal block with intrathecal procaine; spinal ligation) indicated that the shift in clonidine's effect from inhibition of the flexor reflex to excitation occurred immediately following spinalization. Spinal ligation did not produce alpha 1-adrenergic supersensitivity at 15 min or 2 hr after transection, as measured by alterations in [3H]prazosin receptor binding or behavioral responses to clonidine. Thus, the shift in clonidine's effects from alpha 2-adrenergic mediated inhibition of the flexor reflex in intact rats to alpha 1-adrenergic mediated excitation in spinalized rats results because spinal transection unmasks clonidine's alpha 1-adrenergic stimulatory effect. Other conditions under which clonidine exerts alpha 1-adrenoceptor mediated excitatory effects on behavior are discussed.     

Efficacy of clonidine in 24 patients with acute mania

The authors treated 24 newly hospitalized patients suffering from acute mania with 450-900 micrograms/day of clonidine, an alpha 2-adrenergic agonist, for 2 weeks. A marked decrease in manic symptoms was observed after 5 and 13 days of treatment in about half of the patients. Early response seemed to predict the final result. Patients with a family history of affective disorder and patients who had had a good response to neuroleptics during a previous manic episode tended not to respond to clonidine. At the doses given, the patients' tolerance to clonidine was excellent: sedation was markedly lower than it is with neuroleptic treatment.     

Polyanalgesic Consensus Conference—2012: Consensus on Diagnosis,Detection, and Treatment of Catheter‐Tip Granulomas (Inflammatory Masses)

Introduction: Continuous intrathecal infusion of drugs to treat chronic pain and spasticity has become a standard part of the algorithm of care. The use of opioids has been associated with noninfectious inflammatory masses at the tip of the intrathecal catheter, which can result in neurologic complications. Methods: The Polyanalgesic Consensus Conference is a meeting of a group of well‐published and experienced practitioners; the purpose of the meeting is to update the standard of care for intrathecal therapies to reflect current knowledge gleaned from literature and clinical experience. An exhaustive literature search was performed, and information from this search was provided to panel members. Analysis of the published literature was coupled with the clinical experience of panel participants to form recommendations regarding intrathecal inflammatory masses or granulomas. Results: The panel has made recommendations for the prevention, diagnosis, and management of intrathecal granulomas. Conclusion: The use of chronic infusions of intrathecal opioids is associated with the formation of inflammatory masses at the intrathecal catheter tip in a small minority of treated patients. Nonetheless, the appearance of these space‐occupying lesions can lead to devastating neurologic sequelae. The prevention, early detection, and successful treatment of intraspinal granulomas are important considerations when offering intrathecal drug therapy to patients with chronic intractable pain.     

Intrathecal Administration of Different Drugs by Programmable Infusion Device in Chronic Pain. A Case Report.

Objective and Importance . The subarachnoid infusion of narcotics by programmable devices in patients with chronic non-malignant pain can be a useful therapeutic method. However, certain side-effects, opioid tolerance or changes in the nature of the pain can lead to failure of the therapy. Clinical Presentation . We present a case report of a woman with both chronic perineal pain and sciatic pain with radiation to her lower limbs caused by failed back surgery syndrome. The pain proved to be resistant to common medical therapy and to spinal cord stimulation. Technique . After surgical implantation of a programmable infusion pump, the patient's leg pain improved with an intrathecal infusion of morphine and bupivacaine. The perineal pain was treated with an infusion of clonidine. The patient therefore needed alternative infusions of both drugs with changes of infusional parameters. Conclusion . The possibility of varying the infusion method of mixed drugs or alternating the drugs is fundamental for successful therapy since neuropathic pain must be considered a dynamic state.     

Prevention of Intrathecal Drug Delivery Catheter‐Related Complications

In an effort to improve the performance of implantable intrathecal drug delivery systems, a group of physicians experienced in the management of such devices reviewed surgical practices and principles that were associated with low catheter‐related complication rates. Clinical study and postmarket data identified physicians whose patients experienced a relatively low rate of catheter‐related complications. Six of those physicians (three anesthesiologists and three neurosurgeons) reviewed the number and types of intrathecal drug pumps and catheters they had implanted, with an emphasis on the specific details of successful catheter implantation techniques. The authors pooled their experiences to reach a consensus on implant techniques that are associated with a low rate of postoperative complications. The authors found that complications were minimized by the use of specific methods for catheter placement that included: a mid‐to‐upper lumbar dural entry level, a shallow‐angle paramedian oblique insertion trajectory, and meticulous catheter anchoring and tunneling techniques. Systemic antibiotic prophylaxis, attention to pump pocket location, and surgical wound closure techniques also were important in reducing the incidence of postoperative device‐related complications. Their experience indicates that specific implantation techniques using a variety of catheters and accessories can be expected to reduce the incidence of complications after implantation of intrathecal drug administration systems.     

The Use of Implanted Programmable Infusion Pumps in the Management of Nonmalignant,Chronic Low‐Back Pain

Objectives. To assess the mode‐of‐use of implanted programmable infusion pumps in patients with nonmalignant, chronic low‐back pain. Materials and Methods. Charts from 101 consecutive eligible patients were analyzed retrospectively. Data were extracted relating to patient demographics, pump mode of infusion and flow rate, and medications used. Results. Morphine was the agent most frequently used and most patients received one medication at each visit. At the last visit, 94.1% of patients were receiving constant‐flow treatment; 90.1% had received such treatment for ≥ six months and 68.3% throughout the entire analysis period. For patients attaining constant‐flow treatment, mean time from implantation to start of such treatment was 2.7 months. Discussion. The results suggest that many patients with nonmalignant low‐back pain could be implanted with a constant‐flow pump when their programmable device needs replacing or, in some cases, at the start of intrathecal treatment. This would reduce costs and the requirement for surgery.     

Analgesic effects of intrathecally applied noradrenergic compounds in the developing rat: differences due to thermal vs mechanical nociception

Peak noradrenergic receptor development in rat spinal cord has been shown to occur around 12 days of postnatal life. The intent of the present study was to examine the development of analgesia produced by spinally applied noradrenergic agonists. The extent to which these drugs modulate pain information evoked by a thermal vs mechanical stimulus in the infant rat was also addressed. Intrathecal norepinephrine resulted in analgesia that was more pronounced against a mechanical than thermal stimulus and more pronounced in 10-day-olds than 3-day-olds. The alpha 2 receptor agonist clonidine produced a dose-dependent analgesia that first appeared at 7 days of age when tested with a thermal stimulus and 3 days of age when tested with a mechanical stimulus. The analgesic effect of clonidine was also greatest at 10 days of age. The alpha 1 agonist phenylephrine was without analgesic effects. The developmental profile of behavioral analgesia correlates with the ontogeny of noradrenergic receptor activity in the spinal cord. The finding that intrathecal norepinephrine produced a more pronounced analgesia against a mechanical rather than thermal stimulus in the adult is supported by our investigation in the infant rat.     

Chemical Stability of Ziconotide‐Clonidine Hydrochloride Admixtures With and Without Morphine Sulfate During Simulated Intrathecal Administration

Objective. To determine the stability of ziconotide–clonidine hydrochloride admixtures with and without morphine sulfate during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. Admixtures of ziconotide (25 µg/mL) and clonidine hydrochloride (2 mg/mL) with and without morphine sulfate (35 mg/mL) were stored in Medtronic SynchroMed® II pumps at 37°. Pumps were sampled immediately after filling and at four additional time points over the course of 28 (ziconotide–clonidine hydrochloride admixture) or 20 (ziconotide–clonidine hydrochloride–morphine sulfate admixture) days. Drug concentrations were determined using high‐performance liquid chromatography. Results. Ziconotide concentration exceeded 97% of initial at all time points when combined with clonidine alone; statistical evaluation indicated that both ziconotide and clonidine concentrations would remain above 90% of initial for more than 60 days. When compounded with both clonidine and morphine, ziconotide and clonidine concentrations declined; statistical evaluation indicated that the ziconotide concentration was 70% of initial after 20 days, and that clonidine would remain 90% stable for 42 days. Morphine was stable in the presence of ziconotide and clonidine. Conclusions. A ziconotide‐clonidine admixture was 90% stable for 60 days (extrapolated), and a ziconotide‐clonidine‐morphine admixture was 70% stable for 20 days.     

Blunted growth hormone response to clonidine in patients with generalized anxiety disorder

Patients with panic disorder or depression have abnormal responses to the alpha 2-adrenergic receptor partial agonist clonidine. Evidence linking anxiety to noradrenergic dysfunction and the presence of anxiety symptoms in both depression and panic suggest that abnormal responses to clonidine in these disorders could be due to the anxiety symptoms. To explore a possible link between "nonspecific" anxiety symptoms and abnormal responses to clonidine, patients with DSM-III-defined generalized anxiety disorder were given intravenous infusions of clonidine hydrochloride. Responses of plasma growth hormone, 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, and psychological states were determined in 11 patients with generalized anxiety disorder and 14 healthy subjects. Clonidine produced significantly smaller growth hormone responses in patients than in healthy controls. The two groups did not differ in 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, or psychological responses to clonidine. These results are compared with data from similar studies on patients with panic disorder and depression. The blunting of the growth hormone response to clonidine in all three disorders could be due to the presence of generalized anxiety symptoms. Subsensitivity of postsynaptic alpha 2-adrenoreceptors may be present in all three disorders; however, there are alternative interpretations of growth hormone blunting in response to clonidine. Blunting was observed in DSM-III-defined generalized anxiety disorder, whether or not the DSM-III-R criterion of excessive worry was also present.     

Noradrenergic modulation of noxious heat-evoked fos-like immunoreactivity in the dorsal horn of the rat sacral spinal cord.

The tail-flick withdrawal reflex commonly is used to study spinal nociceptive mechanisms; noradrenergic agonists administered intrathecally inhibit the tail-flick reflex in a dose-dependent manner. The objectives of the present study were: (1) to use fos-like immunoreactivity as a marker for neuronal activity to examine the population of neurons in the spinal cord dorsal horn that are engaged by activation of nociceptive tail afferents, and (2) to determine whether fos-like immunoreactivity can be modulated by intrathecally administered alpha adrenoceptor agonists. Neurons demonstrating heat-evoked fos-like immunoreactivity were identified bilaterally in the sacral spinal cord in superficial and deep dorsal horn laminae. Heat-evoked fos-like immunoreactivity was inhibited dose-dependently by intrathecal norepinephrine (NE). The inhibition was attenuated significantly by: (1) phentolamine (PHEN), a nonselective alpha adrenoceptor antagonist; (2) yohimbine (YOH), an alpha-2 adrenoceptor antagonist; and (3) prazosin (PRAZ), an alpha-1 adrenoceptor antagonist. Thus, both spinal alpha-1 and alpha-2 adrenoceptors mediate the inhibition of heat-evoked fos-like immunoreactivity produced by intrathecal NE. ST-91, an alpha-2 adrenoceptor agonist, also inhibited significantly the expression of fos-like immunoreactivity; the inhibition was antagonized by YOH. In the absence of noxious heat, intrathecal NE dose-dependently evoked the expression of fos-like immunoreactivity in the superficial dorsal horn, which was antagonized by PHEN and PRAZ, but not by YOH, suggesting that the effect is mediated by spinal alpha-1 adrenoceptors.