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APS Bulletin • Volume 6, Number 3, May/June 1996

Innovations in Practice

Richard B. Patt, MD, Department Editor

Long-Lasting Sensory Blockade by an Epidurally Injected Material-Based Drug Delivery System

Hendrikus H.M. Korsten, MD PhD; Ren J.E. Grouls, PharmD

This article describes the effects of the epidural administration of suspensions of local anesthetics in animals and in humans. We have found promising results after the epidural administration of a 10% n-butyl-p-aminobenzoate (BAB) suspension (Tween 80 in saline) in patients with intractable cancer pain (Figure 1). Long-lasting segmental analgesia occurs without motor block. The BAB suspension presumably acts as an epidural slow-release depot formulation. In search of an explanation for the differential effect after epidural BAB, we injected dogs with a similarly formulated 10% suspension of lidocaine base. This injection resulted immediately in complete motor blockade and anesthesia. From these studies, we conclude that the unique physicochemical properties of BAB (i.e., very low pKa and very low solubility in water) are important factors for understanding the differential selective block that follows epidural administration. Our work and that of others suggest that the epidural deposition of material-based drug delivery systems may serve as an important method for the treatment of intractable pain. Drugs previously considered unsuitable for clinical use because of their physicochemical characteristics (e.g., insolubility in water) may in fact have important applications when injected in a suitable form (e.g., a suspension).

FIGURE 1. Scanning electron microscopic (SEM) picture of BAB particles in suspension, after application of a gold layer of 7 nm (electron beam energy 10.3kV, magnification 1930, Philips SEM).

A black or white dash on the dashed black and white line indicates a distance of 10 mm.

Figure 1

Analgesia without motor blockade

For more than 100 years, scientists have tried unsuccessfully to develop a local anesthetic that produces analgesia without motor blockade. Currently available formulations of local anesthetics administered epidurally or intrathecally in clinically useful concentrations produce motor block to various degrees and cause problems with voiding. In addition to difficulties in achieving selective local anesthetic-mediated analgesia, the finite duration of effect limits the utility of currently available preparations.

Infusing a local anesthetic continuously through an intrathecal catheter-common practice in postsurgical patients-can extend the duration of analgesia. Recently, however, the U.S. Food and Drug Administration (FDA) limited the use of intrathecal infusions of local anesthetics because of episodes of severe neurologic deficit following their use through microcatheters.

In Europe as well as in North America, continuous epidural or intrathecal infusions of dilute solutions of local anesthetics, combined with opioids, are used to treat pain due to cancer. However, discomfort, inconvenience, catheter-related problems, limited efficacy, the development of tolerance, and logistical problems with home care have tempered initial enthusiasm. Intrathecal or epidural neurolytic blocks with alcohol or phenol are variably effective and may cause serious side effects, such as neuritis, motor dysfunction, and bowel or bladder dysfunction (Twycross & Lack, 1984).

Shulman (1987) administered a suspension of the local anesthetic n-butyl-p-aminobenzoate to patients with intractable cancer pain. This resulted in sustained pain relief without neurological deficits in the majority of patients, and Shulman postulated that slow release of BAB was responsible for the long-lasting effect. Shulman's pioneering work suggested that sustained-release drug formulations deposited in the epidural space produce long-lasting analgesia, without the need for pumps or implantable devices.

In the last decade, sustained-release formulations emerged for a variety of drugs administered by many routes, with the notable exceptions of the epidural and intrathecal routes. The United States Pharmacopoeia (USP, 1990) and the European Pharmacopoeia (1983) require that epidural and intrathecal injections be absolutely without particles and, thus, exclude material-based sustained-release formulations.

We used dogs to test a new formulation of BAB suspension that fulfilled all the special demands for epidural administration (except for the fact that it contained particles). We demonstrated that the epidural administration of BAB induces not only sustained pain relief but also long-lasting sensory blockade, comparable to the transient sensory effects of 0.5%-1.0% lidocaine but without significant motor blockade (Korsten et al., 1990) (Figure 2).

FIGURE 2. Epidural dorsal subcompartment seen from the front, after removal of vertebral bodies, dural sac, and sinal roots.

Thirty-six days after its epidural administration, BAB is found in repeating metamerical regions in the dorsolateral epidural subcompartments.

Figure 2

Testing the new treatment

Encouraged by these results in animals and by Shulman's (1987) work in humans, and after receiving approval from the hospital ethics committee, we proposed this new treatment to 12 patients with advanced cancer and intractable pain. The patients gave informed consent after receiving a thorough explanation of the nature of the experimental treatment and the possible consequences of the epidural administration of BAB. We emphasized, both orally and in writing, that experience with this new suspension was limited and that complications could occur, although we would make all possible efforts to prevent serious complications such as interference with micturition and defecation and paralysis. Before receiving the epidural administration of BAB, all but one of the patients had received treatment consisting of oral opioids and analgesics in combination with epidural morphine alone or sufentanil in combination with bupivacaine, either as a single injection or by continuous infusion. Only when this treatment had failed and estimated life expectancy had diminished to several months did we propose treatment with epidural BAB. One patient refused a long-term epidural catheter for opioid administration and had palliative radiotherapy to reduce pain, but despite this treatment, the tumor mass and the pain increased. This patient also received epidural BAB, because she was in severe pain and her life expectancy was short.

Seven males and 5 females were studied (median age = 62 years; range = 29-75 years) (Korsten et al., 1991). The median time between diagnosis of cancer and treatment with BAB was 42 days. The median TNM classification, a system that utilizes tumor size, node involvement, and prevalance of distant metastases to determine stage (a classification that predicts clinical course), increased from T2NlM0 (stage II) at the time of diagnosis of the cancer to T4N2Ml (stage IV) at the time of treatment for pain with BAB.

Pain involved different body sites and frequently interfered with daily activities and sleep. In addition to treatment with daily epidural doses, patients received a variety of oral analgesics, sedatives, tricyclic antidepressants and corticosteriods. The patients' median daily epidural doses were 21 mg morphine (range = 0-500 mg) over a median duration of 21 days (range = 0-169 days). All patients had lost at least 10% of their body weight in the previous 12 months. As one of the metabolites of BAB is para-amino-benzoic acid, which is allergenic, we specifically determined that no patients were allergic to local anesthetics, drugs, foods, or sunburn lotions.

Treatment with epidural BAB (usually administered via a catheter) terminated when the patient reported adequate pain relief or when no further improvement or increase in sensory blockade was apparent after repeated injections. The highest cumulative volume of epidural BAB administered was 130 ml (13 g BAB). We examined the catheter tips for bacterial contamination after removal.


Findings

In all patients, one or more segmental levels manifested pain relief 24 hours after the first BAB administration. However, all patients required more than one epidural administration of BAB, because the resulting analgesia was not extensive and pain relief was insufficient. Repeated injections resulted in extension of dermatomal analgesia in all patients. We were able to stop epidural infusions in all patients, and sensory blockade and pain relief persisted until death in 10 out of 12 patients (median duration = 29 days; range = 6-133 days). Of the 9 patients who were discharged, 8 died at home. This was remarkable, as all of the patients had been hospitalized for management of intractable pain. The only readmission, which was for severe dyspnea and not pain, died 2 days after hospitalization.

Discussion

The study demonstrated that repeated epidural administrations of BAB produced pain relief of up to 6 months in cancer pain patients, a result consistent with Shulman's (1987) findings. In addition to a marked reduction in pain and in opioid use, we demonstrated sensory blockade to pinprick and cold discrimination with no evidence of motor blockade for up to 6 months. This latter finding is consistent with results from our previous work with epidural BAB in dogs (Korsten et al., 1990). In the animal model, we demonstrated a significant increase in stimulation threshold to electric current without concurrent motor blockade for days after repeated epidural BAB administrations.

Our observations of durable sensory analgesia in the absence of motor effects are at odds with those of Shulman (1987) in dogs and in humans, as he reported only short-lived sensory blockade for 3 to 4 hours in dogs and for 1 hour or less in humans after the epidural administration of BAB. This difference in clinical effect is difficult to understand because in both studies investigators used the basic chemical substance of BAB-the base form, and not its picrate salt-to make the 10% BAB suspension. Thus, there was probably no chemical difference in the substances used.

However, there are four distinct differences between Shulman's (1987) method and our method:

  1. Shulman used polyethylene-glycol 3350 as a suspending agent, while we used the nonionic surfactant polysorbate 80 to make the suspension.
  2. The size of the BAB particles in suspension differed in that we obtained a median particle size of 15 mm, whereas Shulman reported a particle size of 40 mm.
  3. Our protocol of epidural BAB administrations also differed in that we administered relatively low volumes (7-17 ml) of BAB on consecutive days, whereas Shulman administered a relatively large volume (25-40 ml), repeating it only if necessary.
  4. In our study, every epidural BAB administration was preceded by the administration of 10 ml 1% lidocaine with epinephrine 1:100,000, and was followed by the administration of a 10 ml saline flush.

Our current research is aimed at explicating this fascinating difference between Shulman's (1987) results and our results. In another study (Korsten et al., 1990), we demonstrated that the epidural administration of a lidocaine-base suspension in dogs produced a profound sensorimotor block and no evidence of differential nerve block. Clinical effects were short-lived in this model, and their duration decreased after repeated injection. We postulate that these results, which are the opposite of those obtained after epidural administration of the BAB suspension, result from major differences in the physicochemical characteristics of the local anesthetics BAB and lidocaine. We conclude that the unique physicochemical properties of BAB (very low pKa and very low solubility in water) are important factors for understanding the differential selective epidural block observed after BAB administration. Understanding the development of selective segmental analgesia after epidural BAB will probably lead to further improvements in the method. We are currently engaged in designing a series of multicenter projects to better characterize dose-response relationships and to develop a technique that will allow treatment to be instituted over the course of a single day.

Conclusion

Research conducted over the last decade has revolutionized the manner in which drugs are delivered today by most routes, but epidural administration requires additional research. Material-based drug delivery systems have numerous advantages over solutions, including the following:

The results after epidural injections of an “old” local anesthetic, n-butyl-p- aminobenzoate, formulated as a material-based drug delivery system in dogs and humans, are fascinating and promising: ultra-long-lasting analgesia (months) without motor blockade. The neurotoxicity of BAB must also be taken into account to explain these findings. Further research will need to define the distribution of BAB after its epidural application and to characterize its toxicity.

References

European Pharmacopoeia (Ed. II). (1983). Gravenhage: Staatsuitgeverij.

Korsten, H.H.M., Ackerman, E.W., Grouls, R.J.E., van Zundert, A.A.J., Boon, W.F., Bal, F., Crommelin, M.A., Ribot, J.G., Hoefsloot, F., & Slooff, J.L. (1991). Long-lasting epidural sensory blockade by n-butyl-p-aminobenzoate in the terminally ill intractable cancer pain patient. Anesthesiology, 75, 950-960.

Korsten, H.H.M., Hellebrekers, L.J., Grouls, R.J.E., Ackerman, E.W., van Zundert, A.A.J., van Heren, H., & Gruys, E. (1990). Long-lasting epidural sensory blockade by n-butyl-p-aminobenzoate in the dog: Neurotoxic or local anesthetic effect? Anesthesiology, 73, 491-498.

Shulman, M. (1987). Treatment of cancer pain with epidural butyl-aminobenzoate suspension. Regional Anesthesia, 12, 1-4.

Twycross, R.G., & Lack, S.A. (1984). Symptom control in far advanced cancer: Pain relief. London: Pitman Publishing Ltd.

United States Pharmacopoeia XXII. (1990). Rockville, MD: U.S. Pharmacopoeial Convention, Inc.

H.H.M. Korsten is in the Department of Anesthesiology at the Pain Clinic and Intensive Care Unit of Catharina Hospital in Eindhoven, The Netherlands. R.J.E. Grouls is associate director in the Department of Clinical Pharmacy at Catharina Hospital.

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