ABSTRACT
BACKGROUND: Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. METHODS: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. RESULTS: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. CONCLUSIONS: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.
Subject(s)
Baclofen/pharmacology , GABA-B Receptor Agonists/pharmacology , Nociception/drug effects , Urinary Bladder/drug effects , Urinary Bladder/physiology , Animals , Baclofen/administration & dosage , Female , GABA-B Receptor Agonists/administration & dosage , Injections, Spinal , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: As the meningeally derived, fibroblast-rich, mass-produced by intrathecal morphine infusion is not produced by all opiates, but reduced by mast cell stabilizers, the authors hypothesized a role for meningeal mast cell/fibroblast activation. Using the guinea pig, the authors asked: (1) Are intrathecal morphine masses blocked by opiate antagonism?; (2) Do opioid agonists not producing mast cell degranulation or fibroblast activation produce masses?; and (3) Do masses covary with Mas-related G protein-coupled receptor signaling thought to mediate mast cell degranulation? METHODS: In adult male guinea pigs (N = 66), lumbar intrathecal catheters connected to osmotic minipumps (14 days; 0.5 µl/h) were placed to deliver saline or equianalgesic concentrations of morphine sulfate (33 nmol/h), 2',6'-dimethyl tyrosine-(Tyr-D-Arg-Phe-Lys-NH2) (abbreviated as DMT-DALDA; 10 pmol/h; µ agonist) or PZM21 (27 nmol/h; biased µ agonist). A second pump delivered subcutaneous naltrexone (25 µg/h) in some animals. After 14 to 16 days, animals were anesthetized and perfusion-fixed. Drug effects on degranulation of human cultured mast cells, mouse embryonic fibroblast activation/migration/collagen formation, and Mas-related G protein-coupled receptor activation (PRESTO-Tango assays) were determined. RESULTS: Intrathecal infusion of morphine, DMT-DALDA or PZM21, but not saline, comparably increased thermal thresholds for 7 days. Spinal masses proximal to catheter tip, composed of fibroblast/collagen type I (median: interquartile range, 0 to 4 scale), were produced by morphine (2.3: 2.0 to 3.5) and morphine plus naltrexone (2.5: 1.4 to 3.1), but not vehicle (1.2: 1.1 to 1.5), DMT-DALDA (1.0: 0.6 to 1.3), or PZM21 (0.5: 0.4 to 0.8). Morphine in a naloxone-insensitive fashion, but not PZM21 or DMT-DALDA, resulted in mast cell degranulation and fibroblast proliferation/collagen formation. Morphine-induced fibroblast proliferation, as mast cell degranulation, is blocked by cromolyn. Mas-related G protein-coupled receptor activation was produced by morphine and TAN67 (∂-opioid agonist), but not by PZM21, TRV130 (mu biased ligand), or DMT-DALDA. CONCLUSIONS: Opiates that activate Mas-related G protein-coupled receptor will degranulate mast cells, activate fibroblasts, and result in intrathecal mass formation. Results suggest a mechanistically rational path forward to safer intrathecal opioid therapeutics.
Subject(s)
Cell Degranulation/drug effects , Fibroblasts/drug effects , Mast Cells/drug effects , Morphine/pharmacology , Receptors, G-Protein-Coupled/physiology , Spine/drug effects , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacology , Animals , Guinea Pigs , Humans , Infusions, Spinal , Male , Models, Animal , Morphine/administration & dosage , Signal Transduction/physiologyABSTRACT
BACKGROUND: We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs. METHODS: Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 µL/hour, or as a continuous infusion (25 mg/mL/20 µL/hour). RESULTS: With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross-sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross-sectional mass area (mm2 ) was: Saline: 0.7 mm2 ; x2: 1.8 mm2 ; x4: 2.7 mm2 ; x1: 2.7 mm2 ; x8: 4.2 mm2 ; Continuous: 8.1 mm2 , with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye. CONCLUSIONS: Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.
Subject(s)
Analgesics, Opioid/administration & dosage , Infusion Pumps, Implantable/trends , Morphine/administration & dosage , Spinal Cord/drug effects , Spinal Cord/pathology , Analgesics, Opioid/adverse effects , Animals , Dogs , Drug Administration Schedule , Female , Infusion Pumps, Implantable/adverse effects , Injections, Spinal/adverse effects , Injections, Spinal/instrumentation , Injections, Spinal/trends , Male , Morphine/adverse effects , Random AllocationABSTRACT
Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures. METHODS: Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50µL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34+/CD45+ cells) were employed and ß-hexosaminidase in cell-free supernatants were measured to assess degranulation. RESULTS: A significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of ß-hexosaminidase. The rank order of drug-induced hMC ß-hexosaminidase release was similar to that for flares. CONCLUSIONS: A variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents.
Subject(s)
Analgesics, Opioid/pharmacology , Analgesics/pharmacology , Cell Degranulation/drug effects , Mast Cells/physiology , Skin/drug effects , Animals , Cells, Cultured , Dogs , Humans , Male , Skin/blood supply , p-Methoxy-N-methylphenethylamine/pharmacologyABSTRACT
BACKGROUND AND PURPOSE: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.v. delivery is a promising route to the brain; however, it is unclear how efficiently antibodies delivered i.c.v. penetrate the cerebrospinal spinal fluid (CSF)-brain barrier and distribute throughout the brain parenchyma. EXPERIMENTAL APPROACH: We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against ß-secretase 1 (anti-BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys. KEY RESULTS: Animals infused with anti-BACE1 i.c.v. showed a robust and sustained reduction (~70%) of CSF amyloid-ß (Aß) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40 nM, resulting in a ~50% reduction of Aß in the cortical parenchyma. In contrast, animals administered anti-BACE1 i.v. showed no significant change in CSF or cortical Aß levels and had a low (~0.6 nM) antibody concentration in the brain. CONCLUSION AND IMPLICATIONS: I.c.v. administration of anti-BACE1 resulted in enhanced BACE1 target engagement and inhibition, with a corresponding dramatic reduction in CNS Aß concentrations, due to enhanced brain exposure to antibody.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/pharmacokinetics , Aspartic Acid Endopeptidases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/immunology , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/cerebrospinal fluid , Aspartic Acid Endopeptidases/immunology , Brain/metabolism , Female , Infusions, Intraventricular , Macaca fascicularisABSTRACT
BACKGROUND: Intrathecal infusion of opioids in dogs, sheep, and humans produces local space-occupying masses. To develop a small-animal model, the authors examined effects of intrathecal catheterization and morphine infusion in guinea pigs. METHODS: Under isoflurane, polyethylene or polyurethane catheters were advanced from the cisterna magna to the lumbar enlargement. Drugs were delivered as a bolus through the externalized catheter or continuously by subcutaneous minipumps. Hind paw withdrawal to a thermal stimulus was assessed. Spinal histopathology was systematically assessed in a blinded fashion. To assist in determining catheter placement, ex vivo images were obtained using magnetic resonance imaging in several animals. Canine spinal tissue from previous intrathecal morphine studies was analyzed in parallel. RESULTS: (1) Polyethylene (n = 30) and polyurethane (n = 25) catheters were implanted in the lumbar intrathecal space. (2) Bolus intrathecal morphine produced a dose-dependent (20 to 40 µg/10 µl) increase in thermal escape latencies. (3) Absent infusion, a catheter-associated distortion of the spinal cord and a fibrotic investment were noted along the catheter tract (polyethylene > polyurethane). (4) Intrathecal morphine infusion (25 mg/ml/0.5 µl/h for 14 days) resulted in intrathecal masses (fibroblasts, interspersed collagen, lymphocytes, and macrophages) arising from meninges proximal to the catheter tip in both polyethylene- and polyurethane-catheterized animals. This closely resembles mass histopathology from intrathecal morphine canine studies. CONCLUSIONS: Continuous intrathecal infusion of morphine leads to pericatheter masses that morphologically resemble those observed in dogs and humans. This small-animal model may be useful for studying spinal drug toxicology in general and the biology of intrathecal granuloma formation in particular.
Subject(s)
Analgesics, Opioid/adverse effects , Catheterization/methods , Drug Delivery Systems/methods , Granuloma/chemically induced , Injections, Spinal/methods , Morphine/adverse effects , Spinal Cord Diseases/chemically induced , Animals , Catheters , Cisterna Magna , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Granuloma/pathology , Guinea Pigs , Magnetic Resonance Imaging , Male , Meninges/pathology , Polyethylene , Polyurethanes , Spinal Cord Diseases/pathologyABSTRACT
OBJECTIVES: Oral clonidine is used to treat hypertension but often produces sedation and severe dry mouth; intrathecal clonidine is used to treat chronic pain but may produce hypotension. This clinical feasibility study was conducted to determine if intrathecal clonidine decreases blood pressure in patients with poorly controlled hypertension. MATERIALS AND METHODS: This prospective, single-arm, open-label study was conducted in ten subjects who were taking at least three antihypertensive medications including a diuretic and had an in-office systolic blood pressure between 140 and 190 mm Hg. On the day of treatment, blood pressure was measured before and after a single lumbar intrathecal dose (150 mcg) of clonidine using an automatic oscillometric device every 10-15 min for four hours. Student's paired t-test was used for statistical comparisons. RESULTS: Maximal reductions in systolic and diastolic blood pressures averaging 63 ± 20/29 ± 13 mm Hg were observed approximately two hours after clonidine administration. Decreases in systolic pressure were strongly correlated with baseline systolic pressure. Clonidine produced a significant decrease in heart rate of 11 ± 7 beats/min. No subject required intravenous fluids or vasopressor rescue therapy, or reported spinal headache. CONCLUSIONS: This is the first clinical study in subjects with hypertension that demonstrates significant and profound acute reductions in blood pressure after a single dose of intrathecal clonidine. Future placebo-controlled, dose-escalating studies are warranted to assess the long-term effects of intrathecal clonidine infusion via an implantable drug pump in patients with treatment-resistant hypertension at risk of stroke or myocardial infarction.
Subject(s)
Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Clonidine/administration & dosage , Hypertension/drug therapy , Spinal Puncture/methods , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
STUDY DESIGN: The effects of a low, local dose of a tumor necrosis factor-alpha (TNF-alpha) inhibitor on neuropathic pain behaviors in a rat chronic constriction injury model were evaluated. OBJECTIVE: To investigate whether a peripherally implanted polymer drug depot can deliver a dose of etanercept sufficient to reduce thermal hyperalgesia and mechanical allodynia in a rat model of neuropathic pain. SUMMARY OF BACKGROUND DATA: TNF-alpha inhibitors reduce pain-associated behavior in experimental models of neuropathic pain. Moreover, systemic injections of TNF-alpha inhibitors have suggested some efficacy in treating sciatic pain in limited, off-label clinical studies. Improvements in these results may be obtained by optimal dosing via targeted, sustained delivery at the site of disc-induced inflammation. METHODS: Unilateral chronic constriction injury was applied to the sciatic nerve of 56 male, Wistar rats. Four groups of animals (n = 7) received 0.5 mL phosphate-buffered saline every 3 days, 0.3 or 3 mg/kg etanercept every 3 days, or gabapentin (60 mg/kg) 1 hour before each behavioral test all via subcutaneous injection. Two groups of animals received 1.5 or 3.0 microg/h etanercept delivered by poly(lactic-co-glycolic acid) (PLGA) millicylinders (1 mm diameter x 10 mm long) implanted near the injured sciatic nerve. One group received a PLGA millicylinder implanted near the injured sciatic nerve. The final group received 3.0 microg/h etanercept via PLGA millicylinder implanted next to the uninjured, contralateral sciatic nerve. RESULTS: A low, local dose of etanercept (approximately 3 microg/h) delivered by a polymer depot significantly reduced (P < 0.05) thermal hyperalgesia for 57 days as compared to polymer depot without drug or an etanercept-loaded depot implanted near the contralateral sciatic nerve, and equivalent to a 10-fold higher dose delivered by repeat subcutaneous injection. CONCLUSION: This preclinical study indicates that delivering TNF-alpha inhibitors by means of a locally administered polymeric formulation provides long-lasting analgesia in an inflammatory neuropathic pain model.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Immunoglobulin G/pharmacology , Sciatica/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Chronic Disease , Disease Models, Animal , Etanercept , Hot Temperature , Hyperalgesia/drug therapy , Male , Physical Stimulation , Rats , Rats, Wistar , Receptors, Tumor Necrosis FactorABSTRACT
Intrathecal infusion of morphine using implantable pumps is an accepted practice for long-term management of chronic pain. Despite clinical benefit, development of tolerance and side-effects associated with intrathecal morphine has prompted investigators to explore alternative opioids such as the potent anilinopiperidine analogs, fentanyl, and sufentanil. Relevant preclinical and clinical literature from the MEDLINE database was used primarily for this review. In vitro, both compounds are stable in solution, but studies have not been conducted using implantable pumps under simulated use conditions (e.g., long-term stability at body temperature). Preclinical studies of limited duration have demonstrated efficacy, but safety-toxicology studies have been limited to intermittent boluses of sufentanil only. Few clinical reports on the use of intrathecal sufentanil or fentanyl for chronic pain are available. Although results confirm potency and efficacy with intrathecal administration, further studies are needed to support the long-term use of either opioid in chronic pain management.
Subject(s)
Fentanyl/administration & dosage , Fentanyl/adverse effects , Pain/drug therapy , Sufentanil/administration & dosage , Sufentanil/adverse effects , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/adverse effects , Chronic Disease , Dose-Response Relationship, Drug , Injections, Spinal , Practice Guidelines as Topic , Practice Patterns, Physicians' , Treatment OutcomeABSTRACT
BACKGROUND: Intrathecal clonidine (ITC) is used clinically to manage neuropathic pain but frequently causes hypotension and bradycardia due to centrally mediated sympatholytic effects. OBJECTIVES: The purpose of this study was to evaluate the cardiac electrophysiologic effects of thoracic ITC and its effects on ischemia-provoked ventricular arrhythmias. METHODS: Twelve mongrel dogs with healed myocardial infarctions and heart failure were evaluated. ITC was delivered locally via catheter to the T2-T4 spinal segments and was dosed to reduce heart rate (HR) by >20% to 25%. Electrophysiologic testing was performed before and after ITC. Transient (4-minute) myocardial ischemia was induced via left circumflex coronary artery occlusion on two separate occasions to provoke ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]). Ischemic episodes were separated by 1 to 2 days, and dogs were randomly assigned to receive ITC or intrathecal saline flush (control) prior to the first or the second ischemic episode. RESULTS: ITC produced significant decrease in HR (31%) and increases in PR interval (22%), Wenckebach cycle length (122%), and atrial and ventricular effective refractory periods (19% and 9%, respectively) but had no significant effect on systemic blood pressure. The occurrence of VT/VF was reduced from 9 of 12 to 3 of 12 dogs when ITC was administered prior to transient myocardial ischemia (P = .04). ITC also blunted ischemia-induced HR increase by 74%. CONCLUSION: ITC reduced ischemia-induced VT/VF in a canine model of healed myocardial infarction with superimposed heart failure and acute ischemia. Results from electrophysiologic testing were consistent with a clonidine-induced reduction in cardiac sympathetic activity from the spinal cord. These data suggest that ITC administration may be a novel approach to treating ventricular arrhythmias.
Subject(s)
Adrenergic alpha-Agonists/administration & dosage , Clonidine/administration & dosage , Heart Failure/therapy , Myocardial Infarction/therapy , Tachycardia, Ventricular/prevention & control , Ventricular Fibrillation/prevention & control , Animals , Blood Pressure/drug effects , Disease Models, Animal , Dogs , Electrophysiologic Techniques, Cardiac , Heart Failure/physiopathology , Heart Rate/drug effects , Injections, Spinal , Ischemic Preconditioning, Myocardial , Myocardial Infarction/physiopathology , Pacemaker, Artificial , Tachycardia, Ventricular/physiopathology , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/therapy , Ventricular Fibrillation/physiopathologyABSTRACT
Intraspinal drug infusion using fully implantable pump and catheter systems is a safe and effective therapy for selected patients with chronic pain. The options for this approach are increasing, as drugs that are commercially available for systemic administration are adapted to this use and other drugs that are in development specifically for intraspinal administration become available. In 2000 a Polyanalgesic Consensus Conference was organized to evaluate the existing literature and develop guidelines for drug selection. The major outcome of this effort, an algorithm for drug selection, was based on the best available evidence at the time. Rapid changes have occurred in the science and practice of intraspinal infusion and a Polyanalgesic Consensus Conference 2003 was organized to pursue the following goals: 1) to review the literature on intraspinal drug infusion since 1999, 2) to revise the 2000 drug-selection algorithm, 3) to develop guidelines for optimizing drug dosage and concentration, 4) to create a process for documenting minimum evidence supporting the use of a drug for intraspinal infusion, and 5) to clarify issues pertaining to compounding of drugs. Based on the best available evidence and expert opinion, consensus recommendations were developed in all these areas. The panel's conclusions may provide a foundation for clinical practice and a rational basis for new research.
Subject(s)
Analgesics/administration & dosage , Analgesics/standards , Decision Support Techniques , Injections, Spinal/methods , Injections, Spinal/standards , Pain/drug therapy , Algorithms , Drug Administration Schedule , Drug Compounding/methods , Drug Compounding/standards , Expert Testimony/methods , Humans , Patient Care Management/methods , Patient Care Management/standards , Practice Guidelines as Topic , United StatesABSTRACT
UNLABELLED: We investigated the safety of midazolam administered by continuous intrathecal infusion in relevant animal models. Preservative-free midazolam was delivered to sheep and pigs by using implanted infusion systems (SynchroMed pumps plus silicone catheters). Sheep received midazolam 5 mg/d (n = 4) or 15 mg/d (n = 7) or saline (n = 2) for 43 days at 125 micro L/h. One sheep received 10 mg/d. Infusion concentrations ranged from 1.7 to 2.5 mg/mL (5 mg/d) and from 2.5 to 5.0 mg/mL (15 mg/d). Pigs were evaluated for toxicity only and received 15 mg/d (n = 2) or saline (n = 1) for 43 days at 125 micro L/h. Behavior, neurologic function, and vital signs were documented. Serum and cerebrospinal fluid chemistry and cytology were evaluated, and histology was performed on spinal cord tissue. Behavior and neurologic function remained normal in all subjects. Gross and microscopic evaluation of spinal tissue revealed mild inflammation surrounding the catheter tract in both the midazolam-treated and the saline-treated groups. This inflammation was likely attributable to the mechanical presence of the catheter. These data demonstrate that continuous intrathecal infusion of preservative-free midazolam at doses up to 15 mg/d were well tolerated. IMPLICATIONS: We investigated the toxicity of preservative-free intrathecal midazolam delivered continuously via implanted infusion systems in sheep and pigs. Doses of 5-15 mg/d were well tolerated. The lack of neurotoxicity observed suggests that intrathecal midazolam may be an alternative for the treatment of intractable pain that is unresponsive to opioids.
Subject(s)
Infusion Pumps/statistics & numerical data , Midazolam/administration & dosage , Midazolam/adverse effects , Animals , Infusion Pumps/standards , Injections, Spinal , Sheep/blood , Sheep/cerebrospinal fluid , Spinal Cord/cytology , Spinal Cord/drug effects , Spinal Cord/metabolism , SwineABSTRACT
OBJECTIVE: To determine the safety of hydromorphone delivered by continuous intrathecal infusion via implanted delivery systems in sheep. DESIGN: Sheep implanted with intrathecal infusion systems were randomly assigned to receive either 1.5, 3, or 6 mg/day hydromorphone HCl or saline control (3 sheep/dose level) at a fixed infusion rate of 1.92 mL/day for 28-31 days. Infusions were initiated approximately 5 days after surgical implantation of the delivery systems (pumps and intrathecal catheters), and investigators were blinded to doses administered. An additional group of sheep (N=3) received hydromorphone (open label) at a dose of 12 mg/day. All animals were examined daily during drug infusion for changes in behavior and neurologic function. Cerebrospinal fluid was analyzed for protein, cytology, and hydromorphone concentration in samples collected prior to and at the end of drug infusion. The spinal cord with the catheter in situ was removed en bloc and fixed in formalin for microscopic analysis. RESULTS: All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and saline-treated animals with one exception. Mild inflammation 5 cm cranial to the catheter tip was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation hydromorphone in the vicinity of the catheter was also presented in saline-treated animals. CONCLUSIONS: Hydromorphone was not associated with inflammatory mass formation in the sheep model. Further studies are necessary to determine whether hydromorphone is a safer alternative to morphine for continuous intrathecal infusion for the treatment of chronic pain.
Subject(s)
Drug Evaluation, Preclinical/methods , Hydromorphone/administration & dosage , Hydromorphone/adverse effects , Infusion Pumps, Implantable , Sheep/blood , Animals , Drug Administration Schedule , Female , Hydromorphone/blood , Hydromorphone/chemistry , Injections, Spinal , Lumbar Vertebrae , Male , Models, Animal , Spinal Cord/drug effects , Spinal Cord/pathologyABSTRACT
BACKGROUND: Despite the extensive use of intrathecal morphine infusion for pain, no systematic safety studies exist on its effects in high concentrations. The authors assessed the effects of morphine and clonidine given 28 days intrathecally in dogs. METHODS: Beagles with lumbar intrathecal catheters received solutions delivered by a vest-mounted infusion pump. Six groups (n = 3 each) received infusions (40 microl/h) of saline or 1.5, 3, 6, 9, or 12 mg/day of morphine for 28 days. Additional groups received morphine at 40 microl/h (1.5 mg/day) plus clonidine (0.25-1.0 mg/day) or clonidine alone at 100 microg/h (4.8 mg/day). RESULTS: In animals receiving 9 or 12 mg/day morphine, allodynia was observed shortly after initiation of infusion. A concentration-dependent increase in hind limb dysfunction evolved over the infusion interval. Necropsy revealed minimal reactions in saline animals. At the higher morphine concentrations (all dogs receiving 12 mg/day), there was a local inflammatory mass at the catheter tip that produced significant local tissue compression. All animals with motor dysfunction displayed masses, although all animals with masses did not show motor dysfunction. The mass, arising from the dura-arachnoid layer, consisted of multifocal accumulations of neutrophils, monocytes, macrophages, and plasma cells. Inflammatory cells and endothelial cells displayed significant IL1beta, TNFalpha, iNOS, and eNOS immunoreactivity. No evidence of bacterial or fungal involvement was detected. There were no other changes in spinal morphologic characteristics. In four other groups of dogs, clonidine alone had no effect and in combination with morphine reduced the morphine reaction. CONCLUSIONS: The authors found that high intrathecal morphine concentrations lead to aseptic intrathecal inflammatory masses. The lack of effect of clonidine and the possible suppressive effects of clonidine on the local reaction suggest the utility of such coadministration.
Subject(s)
Analgesics, Opioid/pharmacology , Morphine/pharmacology , Adrenergic alpha-Agonists/administration & dosage , Adrenergic alpha-Agonists/pharmacology , Analgesics, Opioid/administration & dosage , Animals , Arousal/drug effects , Behavior, Animal/drug effects , Blood Pressure/drug effects , Clonidine/administration & dosage , Clonidine/pharmacology , Dogs , Dose-Response Relationship, Drug , Drug Combinations , Heart Rate/drug effects , Inflammation/chemically induced , Inflammation/pathology , Injections, Spinal , Male , Morphine/administration & dosage , Psychomotor Agitation/psychology , Psychomotor Performance/drug effects , Respiratory Mechanics/drug effects , Spinal Cord/pathologyABSTRACT
BACKGROUND: The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep. METHODS: Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis. RESULTS: Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components. CONCLUSIONS: The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.
Subject(s)
Analgesics, Opioid/administration & dosage , Analgesics, Opioid/toxicity , Morphine/administration & dosage , Morphine/toxicity , Analgesics, Opioid/cerebrospinal fluid , Animals , Biotransformation , Cisterna Magna/metabolism , Dose-Response Relationship, Drug , Female , Hindlimb/physiology , Infusion Pumps, Implantable , Injections, Spinal , Lameness, Animal/chemically induced , Male , Morphine/cerebrospinal fluid , Sheep , Spinal Cord/pathology , Subarachnoid SpaceABSTRACT
Nonopioid analgesics are often coadministered with intrathecal morphine to increase efficacy. The purpose of this study was to evaluate stability and compatibility of morphine-clonidine admixtures with an implantable infusion system that is commonly used to treat pain patients. Infusion systems were filled with admixture and maintained at 37 degrees C for 90 days. Samples were collected monthly. Drug concentrations were determined using stability-indicating, high-performance liquid chromatography. For compatibility testing, individual materials comprising the fluid pathway of the device were immersed in clonidine solution and stored at 37 degrees C for various periods through 64 weeks and mechanical performance evaluated. After 3 months of containment in the infusion system, morphine and clonidine concentrations remained at > or = 94% of the theoretical starting concentrations. All device materials retained acceptable mechanical performance following clonidine exposure. These results demonstrate that morphine and clonidine are stable when combined in aqueous solution maintained at body temperature in an implantable infusion system for at least 3 months.
Subject(s)
Analgesics, Opioid/chemistry , Analgesics, Opioid/therapeutic use , Analgesics/chemistry , Analgesics/therapeutic use , Clonidine/chemistry , Clonidine/therapeutic use , Drug Incompatibility , Drug Stability , Infusion Pumps, Implantable , Morphine/chemistry , Morphine/therapeutic use , Pain/drug therapy , Analgesics/administration & dosage , Analgesics, Opioid/administration & dosage , Clonidine/administration & dosage , Drug Therapy, Combination , Humans , Morphine/administration & dosageABSTRACT
OBJECTIVES: The phenomenon of inflammatory masses at the tips of intrathecal drug administration catheters was the subject of a recent case-compilation report and a number of animal studies. We sought to synthesize current clinical and preclinical data to formulate hypotheses about the etiology of catheter-tip masses. METHODS: We reviewed the published human clinical data, new unpublished clinical data, and the results of preclinical studies in two mammalian species, beagle dogs and sheep. RESULTS: Intrathecal morphine sulfate studies in beagle dogs suggested that the observed inflammatory reaction was dose or concentration dependent. Masses occurred after 28 days in one of three animals at 1.5 mg/day (the lowest morphine dose tested); in two of three animals at 3 and 9 mg/day; and in three of three animals at 12 mg/day. The addition of various amounts of clonidine to 1.5 mg/day of morphine revealed no mass formation when the clonidine dose was>0.25 mg/day. A morphine sulfate study that was performed in sheep using a commercially marketed drug administration system found catheter tip masses in two of three animals that received 12 or 18 mg/day of morphine, the highest doses tested. Human cases have occurred only in pain patients who received intrathecal opioids, alone or mixed with other drugs, or in patients who received investigational agents (such as superoxide dismutase or the partial micro-opioid-receptor agonist, tramadol) that were not labeled for long-term intrathecal use. DISCUSSION/CONCLUSIONS: The evidence suggests that the long-term administration of opioids, especially morphine, caused the masses that were observed in humans and in two species of animals. A relationship probably exists between mass formation and intrathecal morphine doses or concentration. Other factors remain to be investigated.