© U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(00)00202-5

Vol. 20 No. 2 August 2000 Journal of Pain and Symptom Management S37

Original Article

Clinical Guidelines for Intraspinal Infusion: Report of an Expert Panel

Gary Bennett, PhD, Kim Burchiel, MD, Eric Buchser, MD, Ashley Classen, DO,Tim Deer, MD, Stuart Du Pen, MD, F. Michael Ferrante, MD,Samuel J. Hassenbusch, MD, PhD, Leland Lou, MD, Jan Maeyaert, MD,Richard Penn, MD, Russell K. Portenoy, MD, Richard Rauck, MD, Mario Serafini, DO, K. Dean Willis, MD, and Tony Yaksh, PhD

Department of Neurology (G.B.), MCP Hahnemann University, Philadelphia, PA; Department of Neurological Surgery (K.B.), Oregon Health Sciences University, Portland, OR ; Anaesthesia and Pain Management Services (E.B.), Hôpital de zone de Morges, Morges, Switzerland; Trinity Pain Medicine Associates, P.A. (A.C.), Ft. Worth, TX; The Center for Pain Relief (T.D.), Charleston, WV; Department of Anesthesia (S.D.P.), Swedish Hospital, Seattle, WA; Pain Medicine Center (F.M.F), University of Pennsylvania Health System, Philadelphia, PA; Department of Neurosurgery (S.J.H.), M.D. Anderson Cancer Center, Houston, TX; Department of Anesthesiology (L.L.), Texas Tech University Health Science Center, Lubbock, TX; AZ St. Lucas (J.M.), Ghent, Belgium; Department of Neurosurgery (R.P.), Mt. Sinai Medical Center, New York, NY; Department of Pain Medicine and Palliative Care (R.K.P.), Beth Israel Medical Center, New York, NY; Pain Control Center (R.R.), Wake Forest University Baptist Medical Center, Winston-Salem, NC; Center for Pain Relief (M.S.), Clarksburg, WV; Alabama Pain Center (K.D.W.), Huntsville, AL; and Department of Anesthesiology (T.Y.), University of California, San Diego, CA, USA

Abstract

Consensus guidelines developed by an expert panel are helpful to clinicians when there is variation in practice and lack of a firm evidence base for an intervention, such as intraspinal therapy for pain. An internet-based survey of practitioners revealed remarkable variation in practice patterns surrounding intraspinal therapy. This prompted an interdisciplinary panel with extensive clinical experience in intraspinal infusion therapy to evaluate the results of the survey, the systematic reviews of the literature pertaining to this approach, and their own clinical experience with long-term spinal infusions. The panel proposed a scheme for the selection of drugs and doses for intraspinal therapy, and suggested guidelines for administration that would increase the likelihood of a successful outcome. These expert panel guidelines were designed to provide an initial structure for clinical decision making that is based on the best available evidence and the perspectives of experienced clinicians.

J Pain Symptom Manage 2000;20;S37–S43.

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

Key Words

Intraspinal therapy, intrathecal, guidelines, clinical practice, decision making

Introduction

Consensus guidelines developed by an ex-pert panel may be helpful to clinicians whenthere is variation in practice and lack of a firmevidence base for an intervention. Intraspinal

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.

S38 Bennett et al. Vol. 20 No. 2 August 2000

therapy is such an intervention. Uncertainty inthe decision-making process surrounding in-traspinal therapy for pain was strongly sug-gested by an internet-based survey of practition-ers, which revealed remarkable variation inpractice patterns (see accompanying paper,page S4). Although this variation will mostlikely diminish as research establishes thesafety and efficacy of specific intraspinal thera-pies, the evidence is currently scant (see sys-tematic reviews, page S12), and guidelines forpractice must rely on the best available dataand clinical experience.

An interdisciplinary panel (see Preface) withextensive clinical experience in intraspinal in-fusion therapy evaluated the results of the in-ternet survey, the systematic reviews of the lit-erature pertaining to this approach, and theirown clinical experience with long-term spinalinfusions. They met in small working groupsand a plenary session to develop treatmentguidelines. There were two primary objectives:1) to propose a scheme for the selection ofdrugs and doses for intraspinal therapy, and 2)to suggest guidelines for administration thatwould increase the likelihood of a successfuloutcome.

Drug Selection for Intraspinal Therapy

The panel’s review suggested that the overallapproach to intraspinal infusion could be con-sidered a hierarchy of therapeutic strategies(see Fig. 1). The first-line approach gains clearsupport from the available data and an ex-tensive clinical experience. Second-line ap-proaches have limited supporting data, but alarge clinical experience supports the use ofthese therapies and they are now commonlyapplied. The third-line and fourth-line strate-gies have clinical promise, but both the scien-tific data and clinical experience are extremelylimited. It may be appropriate for experiencedclinicians to consider these approaches inhighly selected cases. The evidence in supportof fourth-line strategies is so meager, however,that only the most extreme clinical situationwould justify treatment. Over and above thesefour levels, the consensus panel listed a finalgroup of drugs which should not be used inclinical practice based on concerns aboutsafety.

First-Line Approach

The mainstay drug for long-term intrathecalinfusion has been morphine and the expertpanel agreed that morphine, as a single entity,should be considered the first-line strategy formost patients. Although randomized trials arelacking, the use of this drug is supported by arelatively large published literature and a longhistory of use.

The expert panel noted that the daily mor-phine doses reported by the physicians re-sponding to the internet-based survey were 1.0–23.5 mg/day. This experience is consistent withthe panel’s opinion that the usual appropriatedose range for intrathecal morphine should be0.2 mg/day to 20 mg/day, with an average start-ing dose of 0.53 mg/day and an average maxi-mum long-term infusion dose of 21.1 mg/day.These conclusions are derived largely frompractical considerations. The lower limit re-flects concerns about daily drug doses that areso low that they are homeopathic and the up-per limit is determined by the desire to main-tain a minimum time (perhaps 2 to 4 weeks)between pump refills. Because the volume ofmost pumps is 18 to 20 mL and the usual maxi-mum compounded concentration of morphineis 50 mg/mL, the maximum dose that can bedelivered between refills is 1000 mg. If refillsare usually administered after 16 to 17 mL havebeen infused, the minimum time between eachvisit is 42 days if the daily dose rate is 20 mg/day. As the interval between refills becomesshorter, the frequency of office visits for refillsand risk of infection increase.

Although consideration of higher-dose mor-phine may be justified in some situations, con-cerns about the need for frequent refills, com-bined with the risk of a drug-related hyperalgesiasyndrome at higher doses,

1

suggest that pa-tients should be considered for an alternativetherapeutic strategy when the required mor-phine dose approaches 20 mg/day. Most pa-tients require more modest doses, and mor-phine concentrations less than 50 mg/mL(e.g., 10–25 mg/mL) are appropriate for thesepatients. The expert panel emphasized thatthe selection of a concentration should con-sider several factors, including pump programcapabilities and the most desirable interval be-tween refills. Given the important opportunityfor monitoring provided by a refill visit, thepanel suggested that the concentration be ad-

Vol. 20 No. 2 August 2000 Clinical Guidelines for Intraspinal Infusion S39

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justed to allow refill visits at least every 4 to 6weeks, and no more than every 2–3 monthsapart. Thus, total drug dose (mg/L) is definedby analgesia and side effect while the desiredrefill interval serves to define drug infusionconcentration.

Drug-pump compatibility and the effects onthe pump from the drug diluents and pH areimportant considerations for all intraspinaldrugs. Morphine has never been associatedwith problems related to these factors, and anextensive clinical experience suggests that solu-tions up to 50 mg/mL are tolerated by thepump and are acceptable for long-term clinicaluse. Nonetheless, the panel noted the lack ofempirical data concerning these factors as aclear gap in the literature pertaining to in-traspinal therapy, including therapy with mor-phine. Although it is generally accepted that apH of 4–5 is compatible with pumps, more in-formation should be acquired for each of thedrugs discussed herein.

Second-Line Approaches

If infusion of morphine alone provides unac-ceptable analgesia, a second-line strategy isneeded. On the basis of the available literatureand a large clinical experience, the expertpanel concluded that several options should beconsidered at this stage. These include 1) thecombination of morphine and the local anes-thetic bupivacaine; 2) the combination of mor-phine and the alpha-2 adrenergic agonistclonidine; and 3) the use of an alternative opi-oid, specifically hydromorphone. Althoughother local anesthetic drugs and opioids can beused intrathecally, the expert panel concludedthat only bupivacaine and clonidine can be jus-tified as second-line approaches for combina-tion with morphine given the published litera-ture and the accumulated clinical experience.

The empirical data supporting each of theseapproaches are very limited (see accompany-ing paper) and there is no systematic informa-tion that would support the use of one approachover another. The expert panel noted that bupi-vacaine and clonidine usually are considered ap-propriate add-ons when the pain syndrome has aneuropathic component. This strategy has wide-spread support among clinicians (see accompa-nying survey). In the event of adequate analgesiabut intolerable opioid-related side effects (e.g.,nausea or pedal edema), an attempt with an al-ternative opioid might be considered the prefer-

able next step before proceeding to a combina-tion of drugs. This strategy, however, reflectsonly anecdotal experience.

The expert panel acknowledged that the rec-ommendation for a morphine combinationwith bupivacaine or clonidine as a second-linestrategy for intraspinal infusion could be usedto justify the use of bupivacaine or clonidine assingle-entity drugs. In the absence of an empir-ical literature concerning these approaches,however, the panel concluded that the single-agent infusion of bupivacaine or clonidineshould be considered only when there is aclear indication (e.g., demonstrated extremesensitivity to opioid-related toxicities).

The optimal dose for morphine when ad-ministered in combination with bupivacaine orclonidine remains unclear. The panel sup-ported a starting dose of 0.5 mg/day for mor-phine when combined with either drug. Inmost situations, the dose will be titrated duringa trial prior to implantation, and subsequentlyduring the course of therapy. The range em-ployed when morphine is administered as asingle entity should guide this titration. In asimilar fashion, the doses of bupivacaine andclonidine usually require titration, both duringthe pre-implantation trial and after long-termtherapy is initiated. The panel noted that thetypical starting dose of bupivacaine is in therange of 2–3 mg/day and the typical maximumdose is 25 mg/day; the dose range of clonidinein this setting is around 50–800

m

g/day.As a single-entity opioid, hydromorphone

may be administered like morphine. Based onthe known relative potency ratio of hydromor-phone and morphine, the usual starting dosefor single-agent hydromorphone is 0.3 mg/dayand the maximum dose for long-term infusionis approximately 12 mg/day. The solubilityproblem that complicates the use of higher-dose morphine does not apply to the same ex-tent to hydromorphone, and higher concentra-tions of this drug are used. As with morphine,hyperalgesia syndrome with hydromorphonecan occur, however, and it is prudent to con-sider a switch to an alternative strategy whenrelatively high doses are required.

Third-Line Approaches

When second-line intraspinal therapy doesnot provide adequate pain relief, the clinicianmight consider a switch to an alternative second-line approach or consider a new set of strategies.

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The expert panel considered the following asthird-line approaches: 1) the combination ofmorphine, bupivacaine, and clonidine; 2) aswitch to an alternative opioid, specifically fenta-nyl or sufentanil; 3) a combination of an alterna-tive opioid, usually hydromorphone but possiblyfentanyl or sufentanil (if previously tried), andone of the non-opioid second-line drugs, specifi-cally bupivacaine or clonidine.

The empirical data supporting these ap-proaches are limited. The expert panel none-theless felt that sufficient experience exists tobelieve that these are reasonable approachesand can sometimes improve outcome for pa-tients who have not responded to more tradi-tional therapies. The use of a combination ofmorphine, bupivacaine, and clonidine is usedwidely (see accompanying paper) and thereare published data concerning the stability ofthis combination. This strategy often is triedfirst for refractory neuropathic pains. In con-trast, an alternative opioid usually is consid-ered when opioid-related side effects under-mine an otherwise effective therapy.

The doses of the more lipophilic drugs fent-anyl and sufentanil that may be used in in-traspinal infusion vary widely. Like hydromor-phone, the solubility of these drugs allows forhigh doses to be administered without theneed for frequent pump changes. Hyperalge-sia has not been reported, but the likelihood ofsystemic opioid toxicity is relatively greatergiven the systemic redistribution associatedwith relatively lipophilic drugs. At this point,experience is too limited to suggest a usualdaily dose range for intrathecal infusion.

Fourth-Line Approaches

If a third-line therapy yields a poor outcome,a change to an alternative third-line approachshould be considered. In very uncommon cir-cumstances, an experienced clinician may de-cide on an approach for which the evidence oflong-term safety and efficacy is very limited andoutcomes related to pump-drug compatibility,drug stability, diluents, and pH are unresolved.The decision to pursue such a therapy, which issupported solely by preclinical data and limitedanecdotal human data, requires a thoughtful re-evaluation of the clinical situation and a discus-sion of the risks and benefits with the patient.

The fourth-line approaches for intraspinaltherapy are best considered in several catego-ries. The first comprises drugs that are in use,

have some limited data supporting safety, butlittle information about efficacy. These include1) meperidine, 2) methadone, 3) ropivacaine,and 4) neostigmine. Given a very small but fa-vorable anecdotal experience, droperidolmight be added to this category. The expertpanel noted that the data supporting the safetyand efficacy of these drugs is sufficiently lim-ited that clinicians should consider an ap-proved institutional protocol before offeringthese approaches on a routine basis.

The second category includes baclofen. Thisdrug is approved for intrathecal use and is ef-fective for spasticity. There is anecdotal evi-dence that it can help when pain is specificallyrelated to spasticity, but evidence that it has abroader analgesic effect is lacking.

The third category includes drugs with un-resolved questions concerning safety, specifi-cally 1) tetracaine, 2) midazolam, and 3) theN-methyl-

D

-aspartate (NMDA) receptor antag-onists such as dextrorphan, dextromethor-phan, memantine, and possibly ketamine.There have been reports associating tetracaineand midazolam with spinal cord toxicity. Al-though midazolam has been used in a largenumber of patients for epidural and brief in-trathecal infusions, the preclinical data are notuniformly reassuring. Similarly, recent animalstudies suggest that the NMDA receptor antag-onists can cause spinal cord injury. The use ofthese drugs should be limited to extreme cir-cumstances or research protocols.

Future Therapies

The review of the expert panel highlightedthe likelihood that other drugs will be consid-ered for intraspinal delivery in the near future.Although some of these drugs could be com-pounded for spinal use now, the publishedpreclinical and clinical literature and clinicalexperience are too limited to endorse theiruse. These drugs include gabapentin, tizani-dine, octreotide, adenosine, aspirin, and zi-conotide (SNX-111). Of these drugs, adeno-sine, octreotide, and ziconotide have animalsafety data, but effects in humans are unclear.

Factors Affecting Medical Decision-Making

Noting the great variation in clinical practicedemonstrated in the internet-based survey of

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practitioners, the expert panel focused on sev-eral key aspects of intraspinal therapy and sug-gested guidelines intended to optimize drugadministration. These recommendations re-flect the experience of the panelists, informedby the systematic review of literature.

Evaluation of Therapeutic Failure

A change from one strategy to another ispredicated on the assessment of therapeutic fail-ure. An intraspinal therapy may fail if intolerableside effects develop, whether or not analgesia isoccurring, or doses of a specific treatment are re-quired that exceed those conventionally used.When this occurs, a comprehensive re-evalua-tion of the patient, including a history and physi-cal examination, is an essential step in clarifyingthe nature of the inadequate response, andthen determining the appropriate therapeuticresponse.

The first step in clarifying the nature of refrac-toriness involves assessment of the pump andother aspects of the infusion system. Computer-ized telemetry can ensure that the programmercan communicate with the pump and the pumpis programmed accurately and performing as in-tended. The pump should be emptied and re-filled, and the volume removed should be com-pared to the expected value determined fromtelemetry. If needed, the pump should be evalu-ated radiographically. Injection of contrast or ra-dionuclide through the pump sideport can de-termine whether there is partial occlusion of thecatheter or a leak at a connection.

If the pump is working appropriately, thepoor therapeutic response presumably involvesone or more factors related to the pain syn-drome itself, or to other patient characteristics.In most cases, the clinical assessment may allowinferences about these processes, but these willnot lead to any specific recommendations fortherapy. The hierarchy of therapeutic strate-gies can help narrow the clinical choices, butthere have been no comparative clinical trialsthat would help the clinician decide on thenext step for treatment. As noted previously,however, therapeutic decisions often are influ-enced by inferences concerning the patho-physiology of the pain (e.g., the early use ofbupivacaine or clonidine if the pain is deter-mined to be neuropathic) and the type of re-sponse observed with prior therapy (e.g., aswitch to an alternative opioid if the analgesic

response is good but opioid side effects com-promise therapy). The experience of the clini-cian, the extent of pharmacy support, reim-bursement considerations, and other factorsalso may influence decision-making.

Occasionally, the evaluation suggests that re-fractoriness may be related to the positioningof the catheter tip at a site too remote from thesegmental level for processing of the nocicep-tive input. If this is suspected, the clinicianmight consider continuing with a relatively hy-drophilic drug, which will have greater spreadthrough the neuraxis than a lipophilic drug.For example, clonidine and bupivacaine havedifferent lipophilicity values and this observa-tion may influence the selection of a second-line strategy.

Dosing

The expert panel noted large practice varia-tions in virtually all aspects of intraspinal dos-ing. To some extent, this variation occurs as aresult of limited experience and insufficientdata from well-conducted surveys and random-ized trials. As an example, the panel noted thatthe internet-based survey revealed remarkabledifferences in how physicians would handlefurther therapy changes in patients with goodanalgesia but uncomfortable side effects dur-ing intraspinal therapy. Similarly, there wereremarkable differences between physicians inthe clinical management of patients with inad-equate analgesia and no/limited side effects.The panel emphasized the need for better sur-veys of outcomes associated with specific inter-ventions and recommended that clinicianswho undertake intraspinal infusion become fa-miliar with conventional dosing guidelines forsystemic opioid therapy.

2–4

These guidelinesmay lead to more informed decision makingduring intraspinal therapy. Adaptation of thelatter guidelines to intraspinal therapy sug-gests, for example, that patients who reportcontinued pain should be considered for doseescalation unless side effects are intolerable ordoses exceed some conventional safe level. Pa-tients with good analgesia but intolerable sideeffects should have the side effect treated andthe dose cautiously lowered. Should pain thenrecur, the need for an alternative treatmentstrategy is confirmed.

As a second example of the need for specificinformation to assist dosing decisions, the

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panel noted the lack of consensus concerningthe approach to opioid dosing when a seconddrug, specifically bupivacaine or clonidine, isadded. Some clinicians always reduce the opi-oid dose, some reduce it only when clonidineis added, and some do not reduce it. The panelendorsed the safest approach, which recom-mends a reduction in the opioid dose when-ever a second analgesic is added.

Conclusion

Advances in pain research and therapy havecombined with the development of sophisti-cated technologies to reveal the extraordinarypotential of long-term intrathecal therapy asan approach to the problem of chronic pain.Unfortunately, clinical capabilities have pro-ceeded quickly and far exceed the scientificunderpinning of these approaches. There is lit-tle information about long-term efficacy andsafety of the numerous drugs that have beenused intraspinally. Important informationabout pump-drug compatibility, drug-drug sta-bility, and the effects of the pH and diluents onvarious outcomes is lacking.

The guidelines proposed by an expert panel

can generate controversy in a field with so littleconsensus. If this controversy encourages cau-tion and drives a critical evaluation of outcomes,it will be a favorable result. At minimum, the ex-pert panel hopes that these guidelines providean initial structure for clinical decision making,which is based on the best available evidenceand the perspectives of experienced clinicians.

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