evidence-based review of the literature on intrathecal delivery of pain medication

© U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(00)00204-9

S12 Journal of Pain and Symptom Management Vol. 20 No. 2 August 2000

Original Article

Evidence-Based Review of the Literature on Intrathecal Delivery of Pain Medication

Gary Bennett, PhD, Mario Serafini, DO, 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, K. Dean Willis, MD, and Tony Yaksh, PhD

Department of Neurology (G.B.), MCP Hahnemann University, Philadelphia, PA; Center for Pain Relief (M.S.), Clarksburg, WV; Department of Neurological Surgery (K.B.), Oregon Health Sciences University, Portland, OR ; Anesthesia 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; Alabama Pain Center (K.D.W.), Huntsville, AL; and Department of Anesthesiology (T.Y.), University of California, San Diego, CA, USA

Abstract

Evidence-based medicine depends on the existence of controlled clinical trials that establish the safety and efficacy of specific therapeutic techniques. Many interventions in clinical practice have achieved widespread acceptance despite little evidence to support them in the scientific literature; the critical appraisal of these interventions based on accumulating experience is a goal of medicine. To clarify the current state of knowledge concerning the use of various drugs for intraspinal infusion in pain management, an expert panel conducted a thorough review of the published literature. The exhaustive review included 5 different groups of compounds, with morphine and bupivacaine yielding the most citations in the literature. The need for additional large published controlled studies was highlighted by this review, especially for promising agents that have been shown to be safe and efficacious in recent clinical studies.

J Pain Symptom Manage 2000;20:S12–S36.

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

Key Words

Evidence-based medicine, intraspinal infusion, pain management, intrathecal

Introduction

To effectively manage pain patients usinglong-term intrathecal infusions, it is importantto understand the strengths and weaknesses ofcurrent and upcoming therapies that havebeen reported in the literature. As part of a

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 Intraspinal Infusion: Evidence-Based Review S13

project to review the role of intrathecal in-fusions, an expert panel conducted a system-atic review of literature concerning the drugsthat have been used in long-term intrathecalinfusion.

Therapies were divided into five general cat-egories of compounds that have been utilized(or hypothesized to be effective) for intrathe-cal delivery of pain medication. The expertpanel then evaluated the safety and efficacy ofeach drug, as well as current clinical practicesand guidelines.

A major goal of the systematic review was tosearch for and evaluate reports of prospectivecontrolled studies examining the safety and ef-ficacy of existing and upcoming therapies—acrucial component of evidence-based medi-cine. Other important criteria in the literaturereview of intrathecal delivery included datafrom preclinical and toxicity studies in bothhumans and animals for the various com-pounds. By critically evaluating these pub-lished reports using widely accepted criteria,the panelists presented a case for the validity ofthe compounds for clinical use. In some cases,the panel suggested further research in ran-domized controlled clinical trials before thetherapy can be adopted for widespread clinicaluse; others, the panel suggested that theremight be no potential for clinical use based onsafety and efficacy considerations. In somecases, there was little or no evidence to supportthe use of specific drugs for intrathecal admin-istration in the treatment of chronic pain.

Methods

Computer literature searches were per-formed using the Medline database for 1966

through October 1999. The searches groupedcitations into 12 groups, as outlined in Table 1.In addition, several specific drugs and drug/drug combination terms were searched (Table2). The panel members then manually scannedthe citation lists from these searches, and cita-tions were marked that potentially provideduseful information about long-term spinal infu-sions. Copies of the selected journal articleswere then obtained, analyzed, and abstracted.Figure 1 shows the abstraction form that wasused for each article to summarize useful infor-mation for reviewing and prioritizing the arti-cles (i.e., study type, drugs, patient type/num-ber, efficacy, and adverse effects).

Table 1

Categories According to Which Literature Search Was Carried Out

1. Drug & (intrathecal or subarachnoid) & (chronic or long-term)—limit to Human, review2. Drug & (intrathecal or subarachnoid) & (chronic or long-term)—limit to Human & (non-review)3. Drug & (intrathecal or subarachnoid) & (chronic or long-term)—limit to Non-human4. Drug & (intrathecal or subarachnoid) & Pain NOT (chronic or long-term)—limit to Human & review5. Drug & (intrathecal or subarachnoid) & Pain NOT (chronic or long-term)—limit to Human & non-review)6. Drug & (intrathecal or subarachnoid) & Pain NOT (chronic or long-term)—limit to Non-human7. Drug & (intrathecal or subarachnoid) NOT Pain NOT (chronic or long-term)—limit to Human8. Drug & (intrathecal or subarachnoid) NOT Pain NOT (chronic or long-term)—limit to Non-human9. Drug & (epidural or intraspinal) & (chronic or long-term)

10. Drug & (epidural or intraspinal) & Pain NOT (chronic or long-term)—limit to Human, English11. Drug & (epidural or intraspinal) & Pain NOT (chronic or long-term)—limit to Non-human, Non-English12. Drug & (epidural or intraspinal) NOT Pain NOT (chronic or long-term)

Table 2

Specific Drugs and Drug CombinationsThat Were Searched in the Database for

Literature Review

Aspirin or acetylsalicylic acid or ASA or salicylic acid or acetylsalicylate

(Baclofen or Lioresal) and painBupivacaine or MarcaineDemerol or Pethidine or Meperidine or DemeralDroperidol or InapsineFentanylClonidineHydromorphone or DilaudidMethadone or MethadonMidazolam or VersedMorphineNeostigmine or ProstigminDextrorphan or Dextromethorphan or MemantineKetamineMK-801Octreotide or VapreotideRopivacaine or Ropivicaine or NaropinSNX-111 or SNX111 or ZiconotideSufentanil or SufentaTetracaineTizanidine

S14 Bennett et al. Vol. 20 No. 2 August 2000

Review of the Literature

This review of the documented experiencewith intrathecal delivery of pain medicationsyielded summaries in five general categories: 1)

opioids, including morphine, hydromorphone,sufentanil, fentanyl, methadone, and meperi-dine; 2) local anesthetics (bupivacaine, ropiv-acaine, and tetracaine); 3) the adrenergic ago-

Fig. 1. Abstraction form for review of published article.


Table 3

Review of Published Articles on Morphine

Name

Ref #

YearType ofPatients

Numberof Patients

MeanFollow-Up

Time(mos)

Outcome

Grade Rating Scale(% of patients) VAS

decrease(T)Excellent Good Fair Poor

Case ReportsOnofrio

29

1981 Cancer 1 5 100%Greenberg

30

1982 Cancer 1 3 100%Mocavero

31

1982 Cancer 1 Bolus 100%Injections

Spaziante

32

1985 Cancer 1 18 100%Frizelle

33

1994 Cancer 1 21 100%VanMelkebeke

34

1995 Non-cancer 1 30 100%Devulder

35

1998 Cancer 1 2.5 100%Tamakawa

26

1998 Cancer 1 6 100%Retroprospective Reports

Wang

36

1978 Cancer 8 Single 75% 25%Injection

Wang

8

1979 Cancer 8 Single 14%Injection

Ventafridda

37

1979 Cancer 38 Single & Multi 78%Injection

Cousins

38

1979 Cancer 5 Single ?100%Injection

Leavens

39

1982 Cancer 2 3.5 50% 50%Rico

40

1982 Cancer 10 Multi 30% 30% 30% 10%Injections

Coombs

41

1983 Cancer 2 3 55%Lazorthes

42

1983 Cancer 9 3.5 90%(Repeated

Injection)Schroeder

43

1984 Cancer 3 Unknown 100%Coombs

44

1984 Cancer 6 7 16% 16% 67%Penn

45

1984 Cancer 12 3.9 50% 42% 8%Cobb

46

1984 Cancer 10 3.9 30% 30% 40%Krames

47

1985 Cancer 11 5.5 27% 27% 45%Meynadier

48

1985 Cancer 25 ?3.9 84% 12% 4%Wang

49

1985 Cancer 46 ??? 52% 48%Paice

50

1986 Cancer 9 7.5 ???Shetter

51

1986 Cancer 14 3 50% 29% 21%Goodman

52

1987 CRPS (RSD) 3 4 33% 33% 33%Ventafridda

53

1987 Cancer 53 1.5 15% 19% 66%Madrid

54

1987 Cancer 35 ??? 44% 34% 40% 11%Penn

55

1987 Cancer 35 5.4 49% 31% 20%Non-cancer 8 21 50% 50%

Brazenor

56

1987 Cancer 26 5 76% 12% 12%Rafii

57

1988 Cancer 3 5 ?100%Non-cancer 1 9 100%

Onofrio

58

1988 Cancer 8 12.7 ?100%Muller

59

1988 Cancer 23 Unknown ?100%Arner

60

1988 Cancer 18 1.5 ?100%Ali

61

1989 Cancer 4 6.3 ?100%Schramm

52

1990 Cancer 25 11 40-60%Onofrio

63

1990 Cancer 53 4 32% 32% 18% 18%Plummer

64

1991 Cancer 17 3 47% 41% 12%Non-cancer 1 1 100%

Andersen

65

1991 Cancer 9 2 89% 11%Follett

66

1992 Cancer 35 8 77% 23%Non-cancer 2 36 50% 50%

Schultheiss

67

1992 Cancer 79 3 ?48% ?48% 4%Krames

68

1993 Non-cancer 3 27 81% 19%Fenollosa

69

1993 Cancer 2 18 UnknownNon-cancer 10 ?36 67% 33%

Chambers

70

1994 Cancer 12 6.2 83% 17%Non-cancer 3 22.3 100%

Devulder

71

1994 Cancer 33 ?2.2 76% 24%

(

continued

)


nists clonidine and tizanidine; 4) N-methyl-D-aspartate (NMDA) antagonists, such as dextror-phan, dextromethorphan, memantine, and ket-amine; and 5) other agents, including soma-tostatin analogs (octreotide and valpreotide);baclofen, ziconotide, midazolam, neostigmine,aspirin, and droperidol.

Opioids

Morphine

During the 1970s, the discovery of spinal opi-oid receptors aroused interest in intrathecaladministration of morphine.

1–28

Three majortypes of opioid receptors (mu-, kappa-, anddelta-) have been identified.

4

The mu-recep-tors mediate the major effects of morphine,such as analgesia and respiratory depression.

5

Though subtypes of the mu-receptors havebeen proposed,

6

no useful drugs have arisenthus far from the hypothesized classification.Other studies have found a high concentrationof these receptors in the substantial gelatinosaof the dorsal horn, a major site for early inte-gration of nociceptive input.

7,8

There are no data on either efficacy or safetyfrom controlled clinical trials investigating in-trathecal morphine. There are, however, numer-ous published case reports and retrospectivestudies with a smaller number of published pro-spective and multicenter studies. In these articles,over 2,000 patients, with chronic cancer and non-cancer pain, are reported to have received in-trathecal morphine (Table 3).

8,26,29–87

Intrathecal morphine is considered to be ap-proximately ten times more potent than thesame amount administered epidurally (i.e., 0.5mg intrathecal morphine produces equivalentanalgesia of 5 mg epidural). Because of thesmall volume of distribution (approximately 70mL), the intrathecal morphine dose yields acerebrospinal fluid (CSF) concentration muchhigher than that which occurs with vascular ab-sorption following epidural administration.

11

Also, since the rate of elimination from the CSFmorphine is similar to the rate of eliminationfrom plasma, the duration of action is relativelylong (apparently due to the high concentrationfound in CSF).

12

Following intrathecal adminis-tration, morphine is not detected in the plasmafor the first 2 hours after injection.

10

Slow rostral

Table 3 (continued)

Name

Ref #

YearType ofPatients

Numberof Patients

MeanFollow-Up

Time(mos)

Outcome

Grade Rating Scale(% of patients) VAS

decrease(T)Excellent Good Fair Poor

Cherny

72

1995 Cancer 4 Unknown UnknownBecker

73

1995 CRPS (RSD)

2 57 50% 50%

Bloomfield

74

1995 Non-cancer 50 39 78% ?11% ?11%Paice

75

1996 Cancer 200 ?14.6 ?52% ?43% ?5%Non-cancer 100 ?14.6 ?52% ?43% ?5%

Winkelmuller

76

1996 Non-cancer 112 40.8 23% 23% 26% 28%Tutak

77

1996 Non-cancer 26 23 50% 27% 19% 4%Gestin

78

1997 Cancer 50 5 ?50% ?50%Sallerin-Caute

79

1998 Cancer 159 3 ?40% ?40% 17% 3%Gilmer-Hill

80

1999 Cancer 9 4.5 ?50% ?50%Prospective Reports

Hassenbusch

81

1995 Non-cancer 18 29 33% 28% 39%Angel

82

1998 Non-cancer 11 27 45% 27% 27%Anderson

83

1999 Non-cancer 30 24 20%Multicenter Reports

Rawal

84

1987 Cancer 70% Unknown UnknownSwedenAnesthDepts.

Yaksh

85

1987 Cancer 133 13 Unknown(130),

Non-cancer(3)

Ballantyne

85

1996 Cancer 186 Unknown 58% Unknown Unknown 6.3%Dahm

87

1998 Non-cancer 323 19.5 Unknown ?88% Unknown Unknown


spread is thought to be responsible for “delayed”respiratory depression.

13–16

This rostral redistri-bution of morphine is one factor associated withthe clearance of morphine from the CSF.

17

Elimination also occurs by vascular absorp-tion via the blood supply to the spinal cord.

18

The similarity between the duration of actionand the rate of morphine recompartmentaliza-tion from the CSF to plasma indicates limitedmetabolism in the spinal cord.

19

In the chronicinfusion situation, the metabolite morphine-6-glucuronide (M-6-G) is thought to play alarger role. M-6-G to morphine ratios varygreatly.

20

In two animal studies, the potency ofM-6-G given intrathecally was 10–45 times thatof morphine.

21–23

The metabolites were foundto enter the CSF from the plasma as well as be-ing created in situ by the brain following in-tracerebroventricular injections.

24

There have been no large-scale, randomizedcontrolled trials investigating intrathecal mor-phine. Anecdotal reports suggest the potentialfor good to excellent pain relief, taking into ac-count morphine’s dose characteristics (Table 4).

Hydromorphone

Few studies of intrathecal hydromorphonefor pain have been performed, and there havebeen no controlled trials. It is likely that in-trathecal hydromorphone is widely used be-cause it is more potent than morphine andtherefore allows longer periods of time be-tween without refills, and causes fewer side ef-fects. Hydromorphone’s potency appears to beabout five times that of morphine, but the side-effect profile is equivalent to or better than thatof morphine.

83

There have not been any spe-cific reports of unexpected side effects in theanecdotal reports that have been published.

Sufentanil

There has been a substantial amount of bothhuman and animal research investigating the

use of sufentanil in the management ofpain.

88–102

Sufentanil is a selective mu-receptoropioid analgesic, the thienyl analog of the4-anilinopiperidine, fentanyl,

88

and is highly li-pophilic.

89

Most of intrathecally administeredsufentanil is cleared from the CSF by diffusionvia the epidural space into the epidural fat,systemic circulation, and diffusion into the spi-nal cord.

Animal data on neurotoxicity are conflictingand warrant caution with intrathecal use ofhigh doses of sufentanil. Intrathecal sufentanilhas been studied in cats, sheep, and dogs forinfusions ranging from 1–28 days.

93–96

No drug-related neurotoxicity was found with low tomoderate repeated doses.

95

Large doses (7.5

m

g/kg) of intrathecal sufentanil in sheep wereassociated with moderate behavioral responses(i.e., agitation, rigidity, vocalization), hind limbweakness, and histologic neuronal changes (e.g.,spongiosis, chromatolysis).

In humans, short-term use of small doses ofepidural or intrathecal sufentanil for postoper-ative or labor pain control has been associatedwith no obvious neurotoxicity. Sufentanil, whendelivered by epidural or intrathecal routes inthese clinical settings, showed comparable paincontrol and similar plasma concentrations re-gardless of the administration route. Side ef-fects consisted of rare early respiratory de-pression, nausea, vomiting, somnolence, andrare urinary retention. However, compared tomorphine, these side effects seemed less fre-quent.

91,97–99

The limited data on long-termepidural or intrathecal use in the treatment ofchronic malignant and non-malignant painsuggest that this drug can be infused withoutclinical signs of neurotoxicity.

During long-term follow-up, intrathecal infu-sion of sufentanil was found to be effective inthe treatment of pain. Side effects were rareand not significantly different from those thatoccur with long-term morphine infusion. Onepossible exception is that there appears to be alower incidence of peripheral edema withsufentanil. Pain control was comparable to pre-vious reports with morphine long-term infu-sion.

100,101,103

Fentanyl

The use of intraspinal fentanyl has been ex-tensively reported.

103–131

However, there are no

Table 4

Morphine: Summary of Dose Characteristics

• Dose may stabilize for long periods• Dose escalation commonly occurs• Dose escalation may have multiple causes (i.e., tolerance

progressive disease)


randomized controlled clinical trials on theuse of epidural or intrathecal fentanyl. Thereare three non-controlled retrospective studiesof the efficacy of “long-term” intraspinal fenta-nyl, and a small study in cancer patients receiv-ing intrathecal fentanyl.

Fentanyl is a highly potent mu-receptor opi-oid agonist with a high degree of lipid solubility.Rapid clearance following intraspinal adminis-tration to the circulation results in clinically rel-evant plasma levels. Even after an epidural bolusor short-term (

,

24 hour) epidural infusion, itis likely that systemic redistribution contributesto fentanyl analgesia.

107,113–116,127,130

Moreover,because of the marked inter-individual differ-ences in concentrations of epidural fentanyl ap-pearing in plasma,

118

results from small studiesthat measure leakage in plasma are difficult tointerpret.

There are three retrospective studies evalu-ating the efficacy of intraspinal fentanyl. Themost extensive study

104

described 551 patientstreated for non-malignant lower-back pain withcontinuous epidural infusion of bupivacaine/fentanyl/droperidol. Most were treated via apump and some via an implanted pump. Mostreceived an infusion of 2 mL/hr containingfentanyl 5 mcg/mL, bupivacaine 9 mg/mL,and droperidol 0.05 mcg/mL. The infusionwas repeated 2–9 times (mean: 6.9) for a totalof 3,108 treatments, over a mean duration of19.8 days (range: 2–81 days). Time between in-fusions ranged from 6 to 184 days (mean: 12days). Pain relief was reported to be “excel-lent” in 73% and “good” in 26.5% of patients;no serious side effects were noted.

Another study

120

described the treatment of40 terminal cancer patients who received in-trathecal fentanyl via an external portablepump up to eleven months. The dose of fenta-nyl was not specified, but no serious complica-tions were observed; supraspinal side effectswere only seen during the first week.

Methadone

There are no randomized, controlled clini-cal trials of methadone given by long-term epi-dural or intrathecal infusion. There are nostudies of any kind of the effects of long-termintrathecal methadone infusions.

Interpretation of the literature on metha-done’s effects

17,124,132–151

is greatly complicated

by the recent discovery that the d-isomer ofmethadone is a moderately potent antagonistof the NMDA receptor (with no significant ac-tivity at the mu-receptor). The l-isomer has triv-ial activity at the NMDA receptor; its analgesiceffects are completely reversible by naloxoneand thus ascribable to the mu-receptor alone.The clinically available methadone in theUnited States (Roxane Laboratories) is the ra-cemic mixture. But the methadone used inGermany,

142

and perhaps elsewhere in Europe,Israel, and other countries, may be the l-iso-mer. Reports in the literature often fail to spec-ify the source of drug, and whether it is thel-isomer or the racemic. The NMDA-blockingaction contributed by the d-isomer in a typicaldose of the racemate is very likely to be clini-cally relevant.

133,146

Meperidine

There has been little information publishedon the use of intraspinal meperidine in thetreatment of pain.

153–158

Meperidine is a syn-thetic phenylpiperidine structure with local an-esthetic-like effects. It is capable of both sensoryand motor blockade, and its local anesthetic-likeeffect is not blocked or reversed by naloxone.There is some evidence that the local anestheticeffect occurs not in the dorsal horn of the spinalcord, but at the actual nerve root levels.

The stability data on meperidine show thatcompared to morphine, it is rapidly eliminatedfrom the CSF. This is due to its higher lipid solu-bility. Following intrathecal delivery, morphineis found to have much higher CSF concentra-tions as compared to plasma concentrations. Be-cause meperidine is more lipid soluble thanmorphine, there is also less cephalad spreadcompared to morphine, owing to its higherlipid solubility.

157

There are no published dataavailable on the compound’s stability for long-term intrathecal use (i.e., within a pump reser-voir at 37

8

C). Anecdotal data indicate it to bestable at 37

8

C for 90 days.Toxicity data are also limited and question-

able. There is one case report of the intrathecalinfusion of meperidine that showed no evidenceof toxicity or adverse effects long term.

158

Potential advantages of meperidine includeits combined opioid and local anesthetic prop-erties, intermediate lipid solubility, and stabil-ity at 100 and 200 mg/cc concentrations. In


limited cases, there has been no overt toxicity,and use of meperidine having a pH near 4.0did not appear to affect pump performance.Anecdotal experience might indicate that a pH

$

4.0 might lessen the likelihood of pump fail-ure. Additional study of this drug is warranted.

Local Anesthetics

Bupivacaine

Bupivacaine is a local anesthetic agent of theamide class. The use of bupivacaine by contin-uous infusion via the epidural or intrathecalroute has gained interest over the past fewyears. At this point, there is a great deal of epi-dural data regarding efficacy, side effects, toxic-ity, stability, and cost-effectiveness when deliv-ered by this method (Table 5). The neuraxialuse of this agent has been primarily in the post-operative patient for pain reduction and in theobstetrical patient to aid in comfort during deliv-ery. The use of bupivacaine by continuous infu-sion in the intrathecal space is becoming morecommon.

159–194

There have been no long-termrandomized prospective studies examiningthe efficacy of bupivacaine in intrathecal ad-ministration.

Neurotoxicity studies suggest bupivacaine issafe in humans at clinically relevant doses forintrathecal use. Toxicity data in animals alsoappear favorable at clinically relevant doses.Studies in dog, cat, and sheep models haveshown no toxicity in concentrations well abovethose used in humans.

174–176

Pharmacokinetic

evaluations

177,178

indicate that the systemic ab-sorption of bupivacaine by neuraxial infusiondoes not appear to be affected by age, coexistingdisease, or gender. Renal disease does not ap-pear to have an effect short term, but no long-term studies are available. Pharmacokinetic andpharmacodynamic properties of bupivacaineare well defined and used to determine appro-priate intraspinal dosing and effect.

195,196

In epidural dosing, studies suggest that thetotal dose is more important than the volumeadministered. Epidural bupivacaine has beenshown to be synergistic with epidural opioids. An-ecdotally, the combination of these two drugs ap-pears to be helpful in reducing rapid sensitiza-tion, reducing side effects, and improving overallpain relief.

197–199

The published opioids adminis-tered with bupivacaine include morphine, fenta-nyl, sufentanil, hydromorphone, methadone, andmeperidine.

199–203

Based on the currently available literature, itappears that intrathecal bupivacaine is a safeand acceptable method for providing pain re-lief in both cancer and non-cancer patients. Atthis point, intrathecal bupivacaine appears tobe a clinically efficacious addition to intrathe-cal opioids. Toxicity studies primarily in cancerpatients appear to show no intrathecal toxicityat clinically significant doses. In a small pro-spective study, Sjoberg and co-workers

172

failedto find neurological deficits associated with in-trathecal bupivacaine and morphine. This wascorroborated in other studies that failed to findclinically significant neurohistologic effects.171

Larger studies indicated that there was rare tox-icity when systemic complaints were analyzed.170

Retrospective analysis185 also indicated lack ofsignificant side-effect risks, directly attributableto bupivacaine.

In another small study with non-cancer pa-tients, addition of bupivacaine to intrathecal opi-oids was more effective than opioids alone.68

Also, Sjoberg and co-workers192 reported in astudy of 53 cancer patients that a bupivacaineand morphine combination was more effectivethan high doses of bupivacaine alone (withlower complication rates than bupivacainealone). In a prospective study of 47 non-cancerpatients, Anderson and Burchiel83 observed a50% response rate after 2 years (i.e., visual ana-log scale, McGill pain questionnaire, chronic ill-ness problem inventory) following intrathecaltreatment of morphine/bupivacaine or hydro-

Table 5Bupivacaine Efficacy Summary Based on

Epidural Experience

• Improved visual analogue scale (VAS), McGill, Chronic Illness Inventory

• Significantly higher patient satisfaction with intrathecal dosing than with epidural, less complications than with epidural infusion

• Bupivacaine spares morphine dosing, oral and intrathecal• Improved sleep, gait, and daily activities• Failure higher with personality disorders, narcotic

dependence, neurotic disturbances, widespread pain patterns, social problems

• Intrathecal treatment provides better relief than epidural infusion: sleeping and walking patterns improved with intrathecal infusion

• Decreased need for opioids and decreased VAS• Improved outcome combined with intrathecal opioids


morphone/bupivacaine. Most reported compli-cations in animal studies suggest problems atplasma levels that would not be seen at clinicallyrelevant doses of intrathecal bupivacaine. Avail-able studies indicate stability in both in vitro andin vivo analysis.

Additional studies are needed to documentstability in an intrathecal pump at body tem-perature. The bacteriostatic properties appearto be favorable as well. This is based on bupi-vacaine being bacteriostatic at clinical concen-trations on multiple bacteriological organ-isms.204–206 Further studies are also needed todefine future use of intrathecal bupivacaine.Studies should include long-term toxicity,long-term neuropathology, and compatibilitystudies when used in combination with otheragents. Further studies are needed also to dif-ferentiate types of pain syndromes for whichbupivacaine is most effective.

RopivacaineRopivacaine is an amide-type local anes-

thetic. The relative affinity of this drug for theA-delta and C fibers over A-beta fibers makes itan excellent choice for analgesia without motorloss. Studies demonstrate that it has less affinityfor motor blockade with effective sensory block-ade when compared to bupivacaine.207,208 Withlower lipid solubility than bupivacaine, it is a bitmore available for spread within the intrathecalspace.209

There is no literature on the safety and effi-cacy of long-term intrathecal use of ropi-vacaine. Most of the reported experience hasbeen with short-term epidural use for postop-erative pain.207–216

There is a fairly large amount of toxicity datain the literature on ropivacaine, in which it ap-pears to be approximately 25% less toxic to theCNS and especially to the cardiovascular systemthan bupivacaine (i.e., comparing epidural in-fusions of either drug at a rate of 10 mg/min,to a maximum dose of 150 to 250 mg).207,210 Ad-verse effects of ropivacaine are similar to that ofbupivacaine and the other local anesthetics.The major advantages of ropivacaine in com-parison to bupivacaine are that it is somewhatless toxic; it is more selective for sensory versusmotor nerves between the sensory and motorblockade, and it has lower lipid solubility re-sulting in greater spinal segmental spread. Itsdisadvantages are that it is less potent than

bupivacaine; it has a shorter duration of ac-tion; it has biphasic time-dependent pharma-cokinetics, with gradually increasing totalplasma concentrations and decreasing totalclearance.

Human data on short-term epidural ropi-vacaine use for postoperative pain (2 mg/mLbegun at a rate of 6 mL/h for 63 to 72 hours ofinfusion in 10 patients) suggests doses some-what higher than bupivacaine would have agreater therapeutic window.208 When it was ti-trated to achieve a stable sensory block, therewas a low incidence of motor block, and ropi-vacaine levels in plasma were well below thetoxic range.

TetracaineTetracaine is an ester-linkage-type local anes-

thetic, similar in structure to procaine. It is re-constituted from commercially available pow-der form, and therefore can be tailored tospecific concentrations from low to ultra-highconcentrations due to its very high solubility inaqueous solutions. Little research has beendone on the long-term intrathecal delivery ofthis drug, but there is some significant re-search on short-term delivery of intrathecal tet-racaine.152

Toxicity from intrathecal tetracaine was sug-gested by several cases of cauda equina syndromeresulting from continuous spinal anesthesia inhumans and animals with tetracaine.152,217,218 Astudy using a rat model to assess maldistributionand sustained concentration suggested that thetoxicity was caused by maldistribution of thedrug, which overwhelmed the buffering capabil-ity of the CNS. Tetracaine’s low pH may increasethe chances of toxicity. Despite its potential ad-vantages, long-term intrathecal use is not sup-ported.

Adrenergic AgonistsClonidine and Tizanidine

Although the a-2–adrenergic agonists tizani-dine and clonidine have been extensively stud-ied in animal models; there are few clinicalstudies.170,219–225,235–258,260 For example, publishedsafety studies with 28-day epidural infusions ofclonidine in dogs revealed no safety issues.238

Controlled trials of epidural use in cancer pa-tients as well as normal adult volunteers exists in


the literature, as does an analgesia study in can-cer patients.225,249,255,256

The predominant side effects reported inthe animal and human reports for both drugsare supraspinal, spinal, and peripheral cardio-vascular effects resulting in a dose-dependentbradycardia and blood pressure changes. Sur-veys and case reports indicated both safety andefficacy, but most were not controlled stud-ies.170,226–233

Tizanidine is not available in the UnitedStates as an injectable agent.234 The animalstudies seem to show a dose-related hypoten-sion, but to a degree less than that ascribed toclonidine. No spinal cord changes were ob-served at doses ten times greater than thera-peutic doses.234–236

Leiphart and co-workers and Levy et al., in arat sciatic nerve model, showed that both intra-thecal morphine and tizanidine were (equally)effective for neuropathic pain,235,257 but Ono andcolleagues, working with a similar model, showedthat clonidine and tizanidine were both superiorto opioids in control of neuropathic pain.258 Inneuropathic models, thermal hyperalgesia andtactile allodynia was reversed by intrathecal a-2–adrenergic agents, including clonidine and tiza-nidine.259

In human volunteers, Eisenach and co-workers249 described the positive results of acontrolled trial of epidural titaridine deliveryfor thermal- or capsaicin-induced pain and hy-peralgesia. Clonidine was also found to be effec-tive in the control of complex neuropathic painstates in a randomized double-blind study of 85cancer patients with morphine rescue (56% suc-cessful response for the clonidine arm vs 5% forplacebo),225 and also by Mercadante and Tum-ber in another report, who proposed a role forclonidine in a cancer pain algorithm.255,256

Those studies that looked at pain character andspecifically at neuropathic pain showed thegreater effect of clonidine in this patient popu-lation. Based on results from controlled studies,additional investigation is warranted.

NMDA AntagonistsGlutamate is the most abundant excitatory

transmitter in the central nervous system. It ex-erts its action principally through the AMPA(adenosine monophosphate) receptor and the

NMDA receptor. The release of glutamate andoccupancy of the NMDA receptor serves to de-polarize the membrane and increase intracel-lular calcium. The opening of the channel maybe prevented by 1) competitively antagonizingthe occupancy by glutamate of the receptor(i.e., drugs AP5 or CPP CGS19755.); 2) block-ing the channel (ketamine, memantine, MK801,or CNS5161); or 3) blocking the allostericallycoupled glycine site (i.e., 7 Cl-kynurenic acidor the drug ACEA 1021).

A wide variety of drugs have been synthesizedthat interfere with NMDA receptor function.The majority of these agents are noncompeti-tive, use-dependent antagonists that block theNMDA ionophore channel.96,146,237,261–314

NMDA delivery by the spinal (epidural or in-trathecal) route has been limited principally tothe use of ketamine. A single case study re-ported using intrathecal administration of thedrug CPP, a receptor antagonist.

Aside from analgesic effects, the spinal deliv-ery of NMDA receptor antagonists has uni-formly produced a dose-dependent incidenceof motor dysfunction characterized by weak-ness and hypotension. Preclinical safety studieshave shown little, if any, spinal toxicity in ratmodels, but extended intrathecal infusionstudies carried out in well-characterized dogand sheep models with MK801, ketamine, dex-tromethorphan, dextrorphan, memantine,and the drug AP-5 revealed certain signs of spi-nal cord parenchymal inflammation and in-jury. It is not clear whether the pathology re-sults from a blockade of the NMDA receptor orwhether it represents an effect of these drugsat other molecular targets. These effects arelikely mediated at the spinal level (interme-diolateral cell column neurons) and reflect theexcitatory role of glutamatergic receptors.237

Lower doses in dogs resulted in minimaleffect289 on motor neuron excitation gener-ated by spinopetal cells and interneurons.

Nonspinal effects resulting from redistribu-tion of intrathecal agent to the vascular poolinclude all of the signs typically observed aftersystemic delivery. These include sedation and ageneral behavioral dysfunction including hy-permobility.

Combined with the results obtained fromone study using intrathecal CPP, the resultswith ketamine emphasize the likelihood thatNMDA receptor blockade can reduce pain.


However, these studies do not adequately dis-sociate the spinal action from the systemic ef-fects of low doses of ketamine. In addition, it isdifficult to determine the role played by possi-ble “local anesthetic-like” action.277,315

Spinal NMDA receptors play an importantrole in post-tissue and nerve injury pain pro-cessing, and in the development of tolerance,but currently available drugs must be consid-ered to have a suspect safety profile. Moreover,redistribution of these agents may result in su-praspinal side effects at therapeutic dose.

Octreotide and VapreotideVery little research has been done on the use

of the somatostatin analogue octreotide in-trathecally for pain, and none has been per-formed for vapreotide.316,317 In anecdotal re-ports, an intrathecal dose of 15 to 20 mg/hrproduced a marked decrease in patient pain.

The preclinical literature on pain mecha-nisms suggests that somatostatin or its analoguescould be useful in the intrathecal treatment ofpain. However, the considerable literature re-lated to the spinal actions of spinal somatostatin(beyond the scope of this review) raises safetyquestions. Additional studies are warranted.

Other AgentsBaclofen

Intrathecal baclofen is a standard therapyfor spasticity. A number of animal experimentshave suggested that gamma amino bulyric acid-A (GABA-B) agonists may be helpful in decreas-ing nociceptive responses. Since safety studiesdemonstrated that intrathecal infusion of ba-clofen posed no direct toxicity issues, these haveled to a number of clinical studies using intra-thecal baclofen for nociceptive pain.318–320 Theintrathecal infusion of baclofen has been rarelyreported to be effective for chronic pain fromcauses other than spasticity. However, a recentreport of 5 patients, followed for 6–20 months,showed an average 76% reduction in pain fromphantom pain, arachnoiditis/epidural scarring,lumbar plexopathy, and sciatic neuropathy.321

ZiconotideZiconotide, or SNX 111, an omega-conopep-

tide, is a 25 amino acid peptide from thevenom of the Conus magus, a piscivorous ma-

rine snail. There is a small but important bodyof literature describing ziconotide.322–328 It is ahighly selective N-type voltage-sensitive cal-cium channel antagonist. These N-type volt-age-sensitive calcium channels (VSCCs) arefound at the presynaptic nerve terminals in thespinal dorsal horn. The presumed mechanismof action of SNX 111 in analgesia is the block-ade of neurotransmitter release at the primaryafferent nerve terminal. There is some evi-dence that opioid receptors are connected tothe N-type VSCC, through a G-protein, and it ispossible that some of the acute effects pro-duced by opioids are mediated by inhibition ofN-type calcium channels.322–324

No data are available on the long-term in-trathecal use of SNX 111 either in humans orin animals. Penn and co-workers described nu-merous adverse effects in 3 patients with in-trathecal infusions of ziconotide, includingnystagmus, dysmetria, ataxia, sedation, agita-tion, hallucinations, and coma. Many of thechanges appeared to require days or weeks toclear after stopping or reducing the dose ofthe drug.330

In animal models of acute and neuropathicpain, ziconotide has been found to be consis-tently effective without the development of tol-erance during seven days of infusion.325,326 Theanalgesic effect and the side effects appear tobe dose-related. Recently, Ridgeway and col-leagues reported that ziconotide was useful inthe treatment of severe spasticity after spinalcord injury.329

MidazolamHuman safety studies have not been done.

Analgesia has been observed in postoperativepatients when midazolam is combined with lo-cal anesthetics or opiates, but only anecdotalreports with subarachnoid administration ofmidazolam and morphine are available onlong-term use.331

Preclinical studies suggest concerns aboutthe safety of midazolam during intrathecal in-fusion.331–334 In one study, Erdine and col-leagues gave rabbits 0.3 mg midazolam (pH3.3) intrathecally for 5 days.332 On light andfluorescent microscopy of transverse spinalcord sections, midazolam was found to causesignificant histologic and spinal cord toxicity.They observed histologic and vascular lesions,fibrosis, and actual cell death associated with


administration of midazolam. Svensson andcolleagues at Uppsala University in Swedenalso showed significant changes in dorsal hornand microglial cells in the animals that weretreated with midazolam.333 Schoeffler and co-workers331 and Edwards et al.334 observed nodifference compared to control when assessingsubarachnoid administration in rats. In theirarticle describing their preclinical data withrats, Schoeffler and co-workers also reportedthat in 2 patients with chronic neoplastic painresistant to morphine, addition of midazolamwas effective in controlling pain.331

These neurotoxicity studies raise seriousconcerns about the use of this drug. Muchmore work needs to be completed prior to rec-ommending midazolam for standard use in in-trathecal pain management.

NeostigmineNeostigmine is an acetylcholinesterase inhibi-

tor and appears to produce consistently effectiveanalgesia in the postoperative setting.335–339 Inrandomized controlled trials, neostigmine causeslittle or no neurotoxicity340,341 although nauseaand vomiting, particularly at higher doses (50–200 mg) have been seen in perioperative and vol-unteer settings.

In sheep, rat, and dog models, neostigmineappears to be a safe compound with no histo-logic or spinal cord toxicity. In the mid 1990s,the preservative-free form of neostigmine wasdiscontinued, leaving only the methyl-propylpa-raben form. Gürün and collaborators342 studiedneostigmine with a methyl preservative formu-lation and found that the chronic intrathecal ad-ministration of neostigmine was safe in ratsand sheep.

Although efficacy and safety trials in peri-and postoperative settings (orthopedics, volun-teer, oncology, and obstetrics) have shownconsistently good outcome with effective anal-gesia, there are, however, no data on long-termuse. Neostigmine may also show promise foruse in adjuvant or co-analgesic therapy.

AspirinThe use of aspirin in the intrathecal manage-

ment of pain has become a focus of attentionrecently.343–354 The mechanism of action for theintrathecal injection of aspirin, which probablyexists at the spinal level, is inhibition of pro-staglandin synthesis, causing dose-dependent

hypoalgesia. Previous studies have shown thatprostaglandins can block endogenous pain con-trol mechanisms by inhibiting the bulbospinalnoradrenergic component of the descending an-tinociceptive system.343

In the human, there have been two retro-spective studies involving a total of 5 cancer pa-tients and 67 non-cancer patients. All patientswere treated with a single intrathecal bolusthat provided pain relief from 1–30 days. It isdifficult to determine if there were any long-term neurologic examinations or side effects ofthese patients after the single injection. The ef-ficacy was 57%, 78%, and 100%.

Human toxicity appeared to be short-termand consisted of generalized fatigue and hallu-cinations at night. More detailed studies involv-ing other patients with long-term follow-up, es-pecially during and after long-term continuousintrathecal infusion, are not available in the lit-erature. Examination of this drug in other ani-mal species for safety has likewise not beendocumented.

DroperidolClinical studies, including two randomized

controlled trials, a retrospective study, and onecase report, have shown that a low dose of dro-peridol given epidurally can potentiate the anti-nociceptive effect of epidural morphine.355–359

Grip and co-workers demonstrated that dro-peridol itself or in combination with morphinehad no antinociceptive effects. They also ex-erted no histopathologic effect on the ratspinal cord.355 This discrepancy between previ-ous clinical findings and experimental painstudies suggests different modes of action ofdroperidol in humans and rat models. Re-search is needed to determine whether epidu-ral administration of the dopamine antagonistdroperidol may be beneficial as supplementarymedication to epidural opioids when tolerancedevelops.

DiscussionClearly, further research in the intrathecal de-

livery of pain medication is warranted. Clinical ef-ficacy in large-scale randomized controlled trialsutilizing intrathecal delivery of most compoundshas not been demonstrated, and variations be-tween study designs make useful comparisons ofexisting studies difficult. Generally, the scientific


quality of the published studies is variable, withresults obtained from limited numbers of pro-spective controlled studies (many with inade-quate patient group size), uncontrolled clinicalstudies, case reports, retrospective studies, andanecdotes. However, clinical use of the agentshas less rigid aims, criteria, and endpoints thanacademic/clinical research. Data on drug inter-actions, toxicity, and long-term safety for severalcompounds is also incomplete. Preliminary re-sults with several promising agents warrant fur-ther study in randomized controlled trials—animportant criterion for evidence-based medicineas well as acceptance into widespread clinicalpractice.

Periodic surveys of the preclinical and clini-cal literature are important in comparing thesediverse data. For example, in their recent,thorough review, Wallace and Yaksh360 dis-cussed classes of spinally delivered analgesicagents (including clinical experience), toler-ance, safety evaluation, drug delivery tech-niques, morbidity and economics of chronicspinal delivery, and patient screening. The ex-pert panel hopes that the evidence-based re-view presented here will also provide a criticaltool that other investigators may use while ac-cumulating clinical experience with promisingcompounds and studying them in randomizedtrials.

Based on this review of the literature, in-trathecal morphine appears to be safe at clini-cal concentrations, and has favorable efficacydata. Limited information on the other opioidclasses also appears favorable from both a toxi-cology and efficacy standpoint, although pub-lished literature supporting this is very limited.Ongoing research and evaluation is needed todefine the best clinical settings in which to utilizethese compounds as an alternative to morphine.While some studies support the clinical use ofmethadone and meperidine, other studies reportpossible concerns with human use on a long-term, continuous infusion basis, and possible in-compatibility with intrathecal infusion pumps.

Bupivacaine is the only local anesthetic thatcurrently has favorable data for both clinical ef-ficacy and toxicology. Other local anestheticsare being used clinically at this time, but re-search is incomplete regarding this practice.Based on the currently available literature,both clinical efficacy and toxicology for cloni-dine appear favorable. Many anecdotal reports

indicate markedly improved outcomes in pa-tients who previously failed opioid infusions assole agents. Combinations of different drugclasses such as opioids/local anesthetics, opio-ids/clonidine, and opioids/local anesthetics/clonidine are currently being used in clinicalpractice. The efficacy reports appear favorable,but are based largely on case studies and retro-spective analysis. No information is availableon the long-term compatibility of these combi-nations.

Several new agents appear to have the inter-est of both practitioners and researchers forthe future treatment of intractable pain disor-ders. Research on gabapentin, aspirin, NMDAantagonists, naloxone, calcium channel block-ers, midazolam, and cyclooxygenase-2 inhibi-tors appear to be on the horizon, and mayeventually lead to the discovery of clinically rel-evant treatments.

Further research is needed to determine thebest clinical application for many of the com-pounds currently used in clinical practice. Dataare limited on the compatibility of drug combi-nations, dose ranges, and long-term safety formany agents currently identified as clinicallyrelevant. Information is also incomplete re-garding the long-term effects of drug combina-tions on intrathecal catheters and infusion de-vices. Hopefully, the information that thepanelists have provided in this critical reviewwill provide a basis and rationale for future evi-dence-based research in the safety and efficacyof promising agents, either singly or in combi-nation, used in long-term intrathecal infusionsfor pain relief.

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evidence-based review of the literature on intrathecal delivery of pain medication

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