future directions in the management of pain by intraspinal drug delivery

© U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(00)00201-3

S44 Journal of Pain and Symptom Management Vol. 20 No. 2 August 2000

Original Article

Future Directions in the Management of Pain by Intraspinal Drug Delivery

Gary Bennett, PhD, Tim Deer, MD, Stuart Du Pen, MD, Richard Rauck, MD, Tony Yaksh, PhD, and Samuel J. Hassenbusch, MD, PhD

Department of Neurology (G.B.), MCP Hahnemann University, Philadelphia, PA; The Center for Pain Relief (T.D.), Charleston, WV; Department of Anesthesia (S.D.P.), Swedish Hospital, Seattle, WA; Pain Control Center (R.R.), Wake Forest University Baptist Medical Center, Winston-Salem, NC; Department of Anesthesiology (T.Y.), University of California, San Diego, CA; and

Department of Neurosurgery (S.J.H.), M.D. Anderson Cancer Center, Houston, TX, USA

Abstract

Management of pain by intraspinal delivery of drugs enables physicians to target specific sites of action. While this novel approach is gaining increasing use, well-designed studies are needed. A major limitation is the lack of published information on existing drugs used for intrathecal delivery. (The strengths and weaknesses of this information are reviewed in the accompanying literature review article.) Promising agents such as bupivacaine, hydromorphone, and morphine/clonidine combinations warrant further research in large prospective (ideally randomized and double-blind) clinical safety and efficacy studies. These studies may provide data for pain management guidelines, such as those included in the preceding paper. Research must also address issues of formulation, chemical stability/compatibility, pharmacokinetics, and toxicology during clinical development and drug approval. Finally, more basic studies and early phase trials of other potential agents for intrathecal pain management (e.g., gabapentin) are needed.

J Pain Symptom Manage 2000;20:S44–S50.

© U.S. Cancer Pain Relief Committee, 2000.

Key Words

intrathecal, intraspinal pharmacology, efficacy, toxicology, future research, pain

Introduction

The control of intractable pain by long-termintraspinal infusion of morphine is a signifi-cant clinical achievement. However, additionalwork is needed. For example, unsatisfactorypain relief from morphine continues in somepatients, due to side effects or lack of efficacy.This has led to investigation of non-morphine

opioids, non-opioid analgesics, and drug com-binations (as discussed in the survey results pa-per). There is now a growing volume of basicresearch, preclinical work, randomized con-trolled trials, prospective series, case studies,and anecdotal reports that focus on intrathecalinfusions of new compounds and combina-tions.

A critical examination of the data support-ing intraspinal use of the major compounds(reported in the survey paper) appears in theaccompanying literature review.

This paper reviews the merits and limitationsof safety and efficacy study methodologies.Moreover, it summarizes the search for future

Address reprint requests to:

Samuel J. Hassenbusch, MD,PhD, Department of Neurosurgery, C-9.075, The Uni-versity of Texas-Houston M.D. Anderson Cancer Cen-ter, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Accepted for publication: May 30, 2000.

Vol. 20 No. 2 August 2000 Future Directions in Intraspinal Drug Delivery S45

agents with a spinal site of action and providesa priority for research directions.

Evaluating Safety of Intraspinal Analgesic Infusion Agents

General Areas of Animal and In Vitro Research

Preclinical research on long-term intrathecalinfusions should focus on drug issues, such asformulation, pH, osmolarity, drug stability,and compatibility of the drug with the deliverysystem. Animal issues include the biological ef-fect for pain relief, pharmacology of the mech-anism for the drug’s effect, toxicology, effectson spinal cord blood flow, and pharmacoki-netic parameters. Testing of the specific agentpreparation should be carried out under well-defined conditions (i.e., good laboratory prac-tice—GLP) thus facilitating potential clinicaldevelopment and availability.

New drug studies must be performed on ani-mals to examine biologic activity (e.g., pain re-lief) upon delivery into the spinal space. Ani-mal models also assess the drugs’ mechanismof action (e.g., receptor or enzyme-mediatedanalgesia) and side effect profile.

Identifying New Sites of Activity in the CNS

There are multiple sites in the dorsal horn thatfuture analgesic drugs could target. These sitesare associated with putative mechanisms that reg-ulate processing of nociceptive information.

Afferent C-fiber terminals.

These terminals re-lease peptides (substance P [SP], calcitoningene-related peptide [CGRP]) and the excita-tory amino acid, glutamate. These substanceshave excitatory effects via specific receptors onsecond-order spinal neurons. Their excitatoryeffects are counteracted by the inhibitory ef-fects of a number of currently used spinalagents (e.g.,

m

and

D

opioids and alpha-2 adr-energic agonists). Other classes of spinalagents are believed to influence the transfer ofinformation from primary afferent C-fibers tospinal second-order neurons (i.e., the N-typecalcium channel inhibitor, Ziconotide).

NK1 or non-NMDA receptors.

These receptorscan cause persistent depolarization, leadingto glutamate release and

N

-methyl-

D

-aspartate(NMDA) receptor excitation. The associated

increases in intracellular Ca

11

activate vari-ous enzymatic pathways, including phospholi-pase A2, nitric oxide synthase, and phosphory-lating enzymes.

Enzymes and receptors (NMDA).

Phosphorylationof NMDA receptors enhances their sensitivityto glutamate, a process that is believed to con-tribute to the phenomenon of pain-evokedcentral sensitization. Down-regulation of thisenhanced sensitivity may be achieved by theactivation of various G-protein coupled recep-tors, such as those activated by opioids andalpha-2 adrenoreceptor agonists, thereby re-versing or diminishing central sensitization.

Cyclooxygenase (COX) products (prostaglandins—PG) and NO.

Prostanoids are formed by con-stitutive COX enzymes (COX 2) secondary tothe membrane release of arachidonic by acti-vated phospholipase. These lipidic acids dif-fuse extracellularly and facilitate terminaltransmitter release by activating specific pros-tanoid receptors. (This also increases theopening of voltage-sensitive Ca

11

channels.)Spinally delivered prostanoid receptor antago-nists and NO inhibitors reduce the hyperalge-sia induced tissue injury.

Kinases.

Increases in intracellular Ca

11

alsoactivate protein kinase A (PKA) and protein ki-nase C (PKC). These, in turn, can phosphory-late spinal NMDA receptors and result in hype-ralgesic states.

Other agents (adenosine A-1 receptor, N-type Ca

11

channel blockers, NMDA receptor blockers).

Thesereceptors and competitors are thought to regu-late or block glutamate release, displaying apotent anti-allodynic effect. Conversely, phar-macologic blockade of spinal GABA

A

andglycinergic receptors yields a prominent allo-dynia. This suggests that the encoding of low-intensity mechanical stimuli as innocuous alsodepends upon the presence of a tonic activa-tion of intrinsic GABAergic and/or glycine-containing neurons.

Development of New Agents for Spinal Delivery

The development of “new” agents for spinaldelivery requires evaluation of several issues in-cluding formulation, stability, compatibility,toxicology, and safety. Most drugs used for spi-

S46 Bennett et al. Vol. 20 No. 2 August 2000

nal delivery in humans were initially deliveredby a systemic route (i.e., most opioids, many lo-cal anesthetics, and agents like clonidine, neo-stigmine, and baclofen). While historical useprovides insights into their anticipated proper-ties, administration into the spinal space ofa drug should lead to it being considered asa new drug Furthermore, a mixture of FDA-approved (albeit often for other routes and/orindications) agents, such as a local anestheticand morphine, or the use of higher concentra-tions, should undergo clinical evaluation.

Formulation properties.

Unlike other routes ofadministration (e.g., IV/IM), intrathecal infu-sions are limited by volume, and expose theCNS to the injectate. Typically, drug formula-tions for this route of delivery employ higherconcentrations than that for systemic delivery,and create specific issues related to solubilityand stability. Moreover, biocompatibility issuesincluding pH, osmolarity, and excipients (dilu-tion solutions) are important. Thus, preclinicalwork has emphasized the importance of main-taining pH in ranges of 4–8 due to the sensitiv-ity of meningeal innervation.

1,2

Another con-sideration is that products used in formulationof systemic agents (i.e., mannitol for lyophiliza-tion), antibacterial products (phenol, alco-hol), or buffering salts (such as glycine), maycontribute to irreversible spinal neurotoxicityafter intrathecal administration.

Infusate stability and compatibility.

Chronic deliv-ery of multiple agents (typically via an implantedreservoir) requires evaluation of the infusate sta-bility including the implant conditions of bodytemperature (37

8

C), and the pump environment(i.e., the metal reservoir and the tubing/connec-tors in the delivery portion). The chemistry (i.e.,degradation of the target molecule), physico-chemistry (e.g., solubility, formulation of micro-precipitates), and molecular alterations resultingfrom modest changes in excipient pH and/or in-teractions with pump materials are also impor-tant. Other considerations include the pH ofthe agents, solubility, and pH effects on eachother and on the pump. An additional issue isthe “stability” of the excipients mixed togetherfor pump delivery; local anesthetics with a highopiate concentration may exhibit unexpectedpH-dependent interactions.

For many of the current drugs or combina-tions, there is little (or no) information on thecompatibility and stability when multipleagents are combined. Furthermore, future re-search in long-term intrathecal infusionsshould include the hardware systems throughwhich the agents will be infused.

Toxicology.

Delivery of agents into the spinalspace often results in local concentrationswhich far exceed levels (and half-lives) notedafter systemic delivery. This may be result inchanges in myelin sheath integrity, cell viabil-ity, and inflammatory reactions (i.e., activationof astrocytes and resident microglial macro-phages). It remains unclear, however, what se-verity of such changes should be important.Some might suggest that any histologicchanges are significant; others believe that theimportant changes are those that are associ-ated with some clinical examination abnormal-ity in the test animal. In preclinical settings,such changes that occur in a graded mannerwith increasing drug dose rates could indicateadverse effect.

3

Additional proposed toxicity mechanisms in-clude growth factors that induce cellular pro-liferation, vasoconstrictors that lead to localischemia, and agents that may initiate hyperex-citability or apoptosis. These may lead to localchemical changes (e.g., extreme pH or hyper-osmotic solutions) or generation of chemicalspecies that mediate cell dysfunction (i.e., met-abolic inhibitors). Preclinical models shouldbe based on these putative mechanisms andendpoints should include changes in neuro-logic function, reactive changes in cerebrospi-nal fluid chemistry, and histopathologic evalu-ations for demyelination, neuronal death, andinflammatory proliferation.

Assessment of safety in animal models.

Several vari-ables reflect the reliability of safety predictions,including route of delivery, concentration ofthe agent in the intrathecal space, and dura-tion of exposure. Thus, the specific animalmodel is relevant and should include at leastone large animal species (i.e., dog, sheep). In-vestigators must design a model that will dem-onstrate suitable, measurable pathology frompotentially toxic agents.

Because toxicity may be concentration-depen-dent, the concentration anticipated for clinical


use should be used in safety trials. For exam-ple, if a compound is animal-tested at 10 mg/ml at a rate of 2 ml/day, alternative clinicaldosing of twice the concentration delivered athalf the rate exceeds the boundaries of safetyinformation from the animal testing. Otherfactors affecting local concentration are dilu-tion of the drug in the cerebro spinal fluid(CSF), and persistent elevated concentrations atlow rates of infusion. Spinal neurotoxicity hasbeen reported following delivery of lidocaineby low volume microbore catheters.

4

This modelused drug concentrations beyond safety limitsdefined from preclinical work with lower con-centrations.

Drug sequence and formulation.

Drug sequenc-ing is the clinical guideline that incorporatesdifferent classes of intraspinal drugs and drugcombinations. Once these are developed, as inthe previous paper, further research enhancestheir effectiveness and clinical utility. Addi-tional refinement could be based on compara-tive clinical studies examining minimum effec-tive doses, effective concentrations for givenpatient states, and ranges of safe and effectivedoses and combinations. In the clinic, an in-crease in concentration is often necessary forthe treatment of patients (i.e., terminally illcancer pain patients), where adequate pain re-lief is more important than concerns of long-term side effects or toxicity.

Only a limited number of agents are ap-proved by the FDA for spinal delivery, andthere is a limited consensus about the utilityand safety of these agents. However, the maxi-mum safety concentration and dose rate ofagents such as morphine is unknown. Also,there is not a complete consensus about theutility of some agents for certain conditions(e.g., baclofen for neuropathic, spasticity-inde-pendent pain). While there may be a tacit ac-ceptance by the medical community, the physi-cian must approach the use of new agents withcare to avoid posing an unacceptable risk tothe patient.

Future Laboratory Research on Specific Agents

Nonsteroidal anti-inflammatory drugs (NSAIDs).

These agents involve enzyme induction mecha-nisms and include the cyclooxygenase type II(COX-2) inhibitor drugs and aspirin. Further

animal study of neurotoxicity and efficacy iswarranted before clinical use.

Gabapentin.

The FDA initially labeled thisdrug as an anticonvulsant, but its use for neu-ropathic pain has grown. (It is often usedorally for neuropathic pain syndromes.) Itsmechanism of action is unknown, althoughsome data suggest that these pentanoids inter-act with a subset of alpha-2 delta subunit-con-taining calcium channels. There is positive pre-clinical evidence that it is compatible withintrathecal delivery in rats. Further animalstudies are needed to determine safety, toxic-ity, and efficacy in other animals. There is nohuman data, and unresolved clinical issues in-clude neurotoxicity, efficacy in neuropathicand somatic pain syndromes, and compatibilitywith intrathecal drug delivery. If laboratory re-search supports intrathecal use, clinical studiesshould be a high priority.

Evaluating Efficacy of Intraspinal Analgesic Infusion Agents

General Clinical Efficacy Studies

The preceding papers in this special sectionindicate a lack of published information, espe-cially in peer-reviewed literature, on manydrugs (and drug combinations) used for long-term intrathecal infusion. A database fromwell-designed safety and efficacy trials for thelong-term treatment of chronic pain using im-plantable infusion pump systems is needed toaid future research. Research should focus onspecific outcome parameters and distinguishbetween various types of pain (e.g., neuro-pathic, nociceptive, or combined syndromes).Other study parameters should include infu-sion rate, drug concentration, lipophilicity,catheter tip location, and pharmacokinetics.

Study design for efficacy determination.

The bestefficacy studies are randomized, double-blind,controlled trials. However, for interventionaltechniques with pharmaceutical agents, well-done prospective series may be acceptable.While large cooperative group trials minimizethe time/effort needed to accrue, evaluate,and publish data from prospective studies,their costs are substantial and may hinder thestudy goals.


Prospective, observational cohort studies areanother alternative to randomized double-blind trials. A major criticism of many pub-lished studies in this field is that their measure-ment tools were neither consistent nor vali-dated. Studies in other clinical settings haveused validated measures for pain, side effects,functional outcomes, and quality of life. Futureresearch in this field should incorporate toolssuch as the symptom checklist (SCL-90),McGill Pain Questionnaire (MPQ), and theBrief Pain Inventory.

Another alternative is the N-of-one study, inwhich the patient is his/her own control; butthere are inherent weakness to this approach.A relatively large number of patients are re-quired to overcome questions of relevance.While such studies produce useful informa-tion, the data are more limited than that ob-tained with randomized prospective studies.

After a group of individual studies have beencompleted, periodic literature reviews couldcritically assess evidence that supports the useof a particular drug for long-term spinal infu-sions. Also, meta-analyses of smaller studies ofcommon design may be useful.

Future Clinical Research on Specific Drugs

First-line therapy—Morphine.

Future research formorphine includes extended evaluation ofpossible side effects and their mechanisms(i.e., hormonal effects). There are some re-ports that intrathecal morphine affects levelsof testosterone, follicular stimulating hormone(FSH), and lutenizing hormone (LH), al-though it remains unclear whether the samechanges might result with the oral or intrave-nous delivery of morphine. Lower extremityedema is another side effect that is worthy offuture study.

Second-line therapies—Hydromorphone.

As reflectedin the present survey, hydromorphone is com-monly used despite little published data aboutits efficacy and side effects. Clinical experienceindicates that systemically administered and in-traspinal hydromorphone both have superiorside effect profiles (compared to morphine).There is also limited information on combina-tions with local anesthetics or alpha-adrenergicdrugs. Well-designed prospective studies shouldhelp define the clinical utility of intrathecal hy-

dromorphone infusions. Indeed, the expertconsensus panel felt strongly that hydromor-phone should be a high priority for research.

Second-line therapies—Bupivacaine.

Further stud-ies with bupivacaine are needed, and as seen inthe preceding papers, there is very limited (ifany) toxicity data concerning intrathecal bupi-vacaine at high concentrations. Indeed, exami-nation of formulations with higher concen-trations appears to be a high priority for drugdevelopment.

Morphine/bupivacaine is a common combi-nation for treating somatic and neuropathicpain. There is little data regarding the compat-ibility of this mixture in a programmable pumpat body temperature, and no information onstability. Other unresolved issues include neu-rotoxicity at different concentrations, and ef-fects of the drug solutions on the pump deviceitself.

Although their optimum dosing and efficacywhen used together is unknown, many clini-cians have promoted this combination for opi-oid-unresponsive patients with neuropathicpain (despite little prospective data—only anec-dote). There are also preliminary data suggest-ing that intrathecal delivery of a morphine/bupivacaine combination results in a slower ratein the development of apparent tolerance.

Second-line therapies—Clonidine.

Research shouldalso examine the long-term compatibility ofdifferent concentrations of morphine/cloni-dine. Future research should compare the effi-cacy of those various combinations in neuro-pathic, somatic, and mixed pain syndromes.Also, delineation of the additive and synergisticeffects of this combination (and its pharmaco-dynamics) requires further research.

Third-line therapies—Other opioids.

While re-search on the safety/efficacy of fentanyl andsufentanil will provide useful information, ithas a lower priority than investigations of mor-phine or hydromorphone.

Third-line therapies—Morphine/bupivacaine/cloni-dine.

There are no data on the compatibilityof this combination in a programmable pumpat body temperature. There is also no pub-lished information on drug combination stabil-ity and possible neurophysiologic effects. Also,


there are no studies comparing efficacy in neu-ropathic and somatic pain.

Fourth-line therapies—Ropivacaine.

Ropivacaine isa relatively new local anesthetic agent which re-quires examination of differential efficacywhere there may be a wider therapeutic win-dow between pain relief and side effects (i.e.,general somatic sensory vs. motor blockade).Until investigators obtain sufficient data, studyprotocols should dictate the clinical use for in-trathecal infusions of ropivacaine

Fourth-line therapies—Meperidine.

Meperidine isthe only opiate which manifests a clinically sig-nificant local anesthetic effect—a theoreticaladvantage. However, there is no definitive in-formation about its compatibility in an im-plantable pump and the potential neurotoxic-ity of normeperidine—a breakdown product ofmeperidine.

Fourth-line therapies—Methadone.

Of the twoisomers of methadone, the d-isomer may pos-sess antagonistic activity against the NMDA re-ceptor. However, further preclinical researchshould be performed.

Fourth-line therapies—Midazolam.

Studies indi-cate that midazolam produces analgesia in sev-eral clinical settings,

5,6

but recent evidenceraises significant concerns about the neurotox-icity of intrathecal midazolam.

7

Additional ani-mal research is needed to resolve this issue.

Fourth-line therapies—NMDA Antagonists.

Recentreports of spinal neurotoxicity in sheep anddog models raise serious concerns about whatwas initially a promising class of drugs for in-trathecal use.

8–10

Based on these studies, NMDAantagonists could cause considerable damagein humans. While research is warranted to con-firm or refute this toxicity issue, clinical in-trathecal use of this class is not encouraged.

On the horizon—Ziconotide.

This drug is still in-vestigational and the data suggest a very nar-row therapeutic window. Research shouldidentify an optimum window and level of clini-cal efficacy in patients with cancer, noncancer,neuropathic, and somatic pain syndromes.

On the horizon—Tizanidine.

Tizanidine may be

an alternative to clonidine, but with a lowerside-effect profile. Research should examinewhether this drug exhibits clonidine-like sideeffects following abrupt cessation of infusion(e.g., hypotension, bradycardia, generalized fa-tigue, and rebound hypertension).

There are several promising agents under in-vestigation at different centers in the UnitedStates. Because they are in the early stages ofresearch, specific therapeutic recommenda-tions for these compounds cannot be made.Indeed, it is not yet possible to prioritize themas candidates for research and development.

Conclusions

The past twenty years have provided signifi-cant advances in the systemic and spinal ap-proaches to analgesic drug delivery. Since theinitial description of the spinal action of opi-oids and alpha-2 agonists 25 years ago (anddemonstration of human efficacy), many spi-nal targets have been described; some havebeen validated in human pain states. Intrathe-cal delivery of drugs directly to the spinal cordnow enables clinicians to target specific sites ofaction where nociceptive signals are encoded.However, the flexibility of this technique is lim-ited by the lack of clinical investigation of theavailable opioids, alpha-2 agonists, and localanesthetic agents.

Research priorities include identification ofnew CNS targets, and the development/testingof new formulations and concentrations ofknown agents for intrathecal administration.Laboratory investigation of stability and com-patibility of single and combinations of multi-ple agents need to be tested under physiologicconditions in the pump environment. Well-designed toxicology studies (in appropriate an-imal and human models) for drugs and im-plantable technologies should also be a fundingpriority. Agents such as hydromorphone andclonidine, which have gained clinical accep-tance in intrathecal therapy, require further in-vestigation in prospective clinical studies.

Clinical inquiry should focus on well-designedrandomized controlled clinical trials wheneverpossible. However, both well-documented, pro-spective studies and carefully designed smallsample outcome studies also provide impor-tant information. Ultimately, multicenter col-laboration to support larger accruals and stan-


dardized clinical trials should be a strategicpriority for national pain management organi-zations.

The sequencing of agents and dose-rangingguidelines provided in algorithms such as theone presented in the preceding paper hold agreat deal of utility for the individual practitio-ner, and provide best practice guidance forpain practitioners as a group. Ideally, the abil-ity to evaluate new agents and new formula-tions of known agents (and combinations) inestablished algorithms may provide knowl-edge that could ultimately reduce or eliminatepain at the point of care.

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