Original Research Articles Intrathecal Midazolam as Supplementary Analgesia for Chronic Lumbar Pain 15 Years Experiencepme_

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1 Pain Medicine 2011; 12: Wiley Periodicals, Inc. SPINE SECTION Original Research Articles Intrathecal Midazolam as Supplementary Analgesia for Chronic Lumbar Pain 15 Years Experiencepme_ Jan Prochazka, MD,* Ales Hejcl, MD, PhD, and Lidmila Prochazkova, MD *Central ICU and Neurosurgical Pain Relief Service, Departments of Neurosurgery and Ophthalmology, Masaryk Hospital, Usti nad Labem, Czech Republic Reprint requests to: Jan Prochazka, MD, Masaryk Hospital, Socialni pece 12A, Usti nad Labem 40113, Czech Republic. Tel: ; Fax: ; No grants or other forms of support. No financial relationships. Abstract Background. The antinociceptive effect of intrathecal midazolam is based on its affecting spinal gamma-amino butyric acid receptors. Objective. To evaluate pain relief in patients with chronic low back pain and failed back surgery syndrome after a single-shot intrathecal administration of midazolam. Design. A prospective, open-label study. Outcome Measures. The analgesic effect was determined using a patient questionnaire during subsequent visits to the pain therapy service. We classified at least a 50% pain reduction with improved quality of life and improved functional condition as a positive outcome. Results. Between 1995 and 2010, we performed 500 administrations: 227 administrations in 57 male patients and 273 administrations in 69 female patients. We performed 81 administrations for chronic low back pain and 419 administrations for failed back surgery syndrome. The average age of our patients was 50 years (range 28 to 86). The dose administered ranged from 2 to 5 mg of midazolam. The analgesic effect lasted 9.7 weeks on average, ranging from 1 week to 3 years; the most common reported duration was between 4 and 12 weeks (3 months). In 65% of patients, we achieved pain relief lasting 4 weeks or longer; in 13%, the administration provided no analgesic effect at all. The incidence of side effects (drowsiness, nausea, headache, or transient worsening of complaints) was rather low. Conclusion. Intrathecal midazolam is a useful supplement to standard analgesic therapy with opioids, non-opioids, or spinal steroids. Key Words. Intrathecal Midazolam; Failed Back Surgery Syndrome; Chronic Low Back Pain; Spinal Analgesia; Off-Label Introduction Chronic low back pain (LBP) and failed back surgery syndrome (FBSS) are serious medical problems with significant health, social, and economic impact. The causes of chronic LBP are usually multifactorial. After excluding the so-called red flags (malignancy, vertebral fractures, herpes zoster, osteomyelitis, or other infectious processes, cauda equina syndrome, disc herniation with radicular pain, and/or leg palsy), the therapeutic approach must always be multidisciplinary and comprehensive: exercise, non-opioid and opioid analgesics, or nonsteroidal anti-inflammatory drugs, antidepressants, various interventions, and/or surgery [1]. However, not all of these patients are suitable or indicated for surgical treatment: in many cases, subjective complaints, neurologic examination, and computerized tomography (CT) or magnetic resonance imaging findings do not match in patients with chronic LBP. Further, LBP can persist in patients who have already undergone surgery and have no indication for another surgery due to a high risk of failure [2]. Even more, pain can persist after spinal surgery despite the absence of any correlates displayed in radiographic examinations. These patients 1309

2 Prochazka et al. change into category FBSS and are candidates for comprehensive pain management in pain therapy centers, which can provide various interventional therapies [3,4]. Therapeutic interventions should be diversified in accordance with the type of pain: either somatic or radicular [5] as pain etiology can be somatic, neuropathic, or mixed, especially in the case of FBSS. Spinal steroids administered by a caudal or intervertebral approach, preferably under fluoroscopic control, are widely used in patients with chronic LBP or FBSS [4,6,7]. However, we have only a few simple, minimally invasive, and low-cost possibilities to treat those patients in whom spinal steroids provide minimal analgesic effect. These patients are subsequently destined for spinal cord stimulation or implantable drug delivery systems both relatively costly methods. Another option for pain treatment is the intrathecal (IT) administration of midazolam [8]. The analgesic effects of spinal midazolam, based on influencing spinal gamma-amino butyric acid (GABA A) receptors on its subunits a2, a3, and a5 have been known since the early 1980s, both in animal models and in human patients [8,9]. The purpose of this study was to evaluate the effectiveness of a single-shot treatment with IT midazolam on pain, quality of life (QoL), and functional improvement in patients with chronic LBP and FBSS. Materials and Methods At our department, we have developed a three-stage algorithm for patients with chronic LBP or FBSS (Figure 1). In the first step, there are local interventions (trigger point injections, sacroiliac joint injections, or facet joint injections). In case the analgesic effect is not sufficient, we proceed to the second step applying epidural steroids through a lumbar or caudal approach. If this second interventional step is not sufficient as well, we proceed to the IT administration of midazolam as a third step. All these interventions are used as a supplement to oral opioids or non-opioid analgesics. In this prospective, open label study, we evaluated the analgesic effects of IT midazolam in patients with chronic LBP or FBSS. In our study, some patients were included in both subgroups: before surgery in the chronic LBP category and after one or more spinal surgeries in the FBSS category. After obtaining written informed consent, midazolam was administered as a single-shot injection in outpatients. We used only preservative-free midazolam (Dormicum F. Hoffmann-La Roche Ltd., Basel, Switzerland), or Midazolam Torrex, Torrex Chiesi Pharma GmbH, Vienna, Austria), and the dose of midazolam was dissolved in 5% glucose or in normal saline up to 3 ml in volume. All administrations were performed with the patient in a recumbent position with a small-gauge spinal needle (we started with 22G, but in 1997, we switched to 25G). After administration, the patients have to be at bed rest for approximately 3 hours before they were released as a prevention of post-dural puncture headache (PDPH) and for vital signs monitoring. The initial dose was always 2 mg of midazolam, and according to the analgesic effect achieved, we increased the dose up to 5 mg in a single injection. These doses correspond to mg/kg of midazolam. The time intervals between subsequent administrations were at least 4 weeks. When we aspirated the cerebrospinal fluid back into the syringe filled with midazolam solution to confirm the correct needle position in the subarachnoid space, we could see a slight turbidity of the solution. This turbidity in otherwise clear solution was most likely caused by precipitation of cerebrospinal fluid (CSF) proteins due to low ph of the solution (ph = 3.3). The analgesic effect was evaluated during subsequent patient visits by specifically asking the patient about the level and duration of the pain relief achieved. The intervals between the administration and a follow-up visit were determined by the patient s individual needs. The follow-up visits came at intervals of 4 weeks to 9 years. In some cases, patients ceased the treatment or had their analgesic therapy doses transiently decreased (we call it analgesic holidays ). We classified at least a 50% pain reduction with improved QoL and improved functional Figure 1 Our three-stage algorithm for interventional therapy in low back pain. SIJ sign = sacroiliac joint pain; TrPs = myofascial trigger points. 1310

3 Table 1 Summary of demographics data Number of Patients (Male/Female) Number of Administrations (Male/Female) Chronic low back pain 10/15 30/51 Failed back surgery 47/54 197/222 syndrome Table 2 Administered dose of intrathecal midazolam Dose (mg) Number of Administrations condition with focus on the overall feeling, quality of sleep, housework, or hobbies capability, etc. as a positive outcome (in accordance with [10]). Before the first IT administration in each patient, fundoscopy was performed in the Department of Ophthalmology; this procedure is a common practice in our hospital to exclude elevated intracranial pressure. It is a simple, noninvasive method that does not expose patients to X-rays during CT examination before lumbar puncture. After midazolam administration, we evaluated the quality of sedation using a four-point scale as follows: 0 = wide awake and alert; 1 = at times drowsy but easily aroused; 2 = somnolent but easily aroused; and 3 = somnolent and difficult to arouse [11,12]. Some early side effects were registered during bedside visits; late side effects were recorded during subsequent visits of the patient to the pain therapy service. Results Between 1995 and 2010, we performed 500 administrations in our department: 227 administrations in 57 male patients and 273 administrations in 69 female patients. We performed 81 administrations in patients with chronic LBP and 419 administrations in cases of FBSS (for summary of the demographic data see Table 1). The average age of our patients at the time of administration was 50 years (range 28 to 86). The dose administered ranged from 2 to 5 mg of midazolam (Table 2). The duration of pain relief is shown in Figure 2. After 62 administrations, we did not see either any pain relief at all, only weak relief (less than 50% pain reduction), or too short a duration of relief (only several days). In 19 cases, we have no information about the extent of analgesia achieved. The most common duration of analgesia was 1 to 3 months after a single spinal injection; in more than 65% of the cases, we achieved a significant pain reduction lasting more than 4 weeks. The incidence of side effects was low. The most common side effects were drowsiness (approximately 30%), headache (<2%), nausea (<2%), and a transient worsening of complaints (5%). We did not see any clinical signs of neurotoxicity (bladder or bowel dysfunction or radiculopathy) following midazolam administration. Discussion Intrathecal Midazolam for Chronic Back Pain Systemic analgesics are effective in most patients with chronic pain; however, in some patients, their effect is minimal. Pain relief in these patients can be achieved by spinal analgesia as well. We examined numerous reviews concerning spinal analgesia, the choice of drugs used and their doses, the route of administration (epidural or Figure 2 Duration of achieved analgesia after single intrathecal administration. 1311

4 Prochazka et al. subarachnoid techniques), possible side effects, and complications (e.g., [13 18]). All these studies and reviews usually discuss continuous IT infusion via an implantable or external pump in postoperative pain management or chronic LBP therapy. We, on the other hand, employ only a single injection administered without any catheter or pump system. In decision to use spinal analgesics, we have to balance between risks (drug s neurotoxicity, side effects) and expected benefits (pain relief, quality of life) [19]. When introducing a new method for spinal analgesia, one must meet the following criteria: the analgesic efficacy must be confirmed by experimental data and clinical experience, the method must be safe and well-tolerated by patients, the method must be easy to perform, and the costs of the method should be reasonable. IT midazolam can meet all of these requirements: its analgesic properties have been confirmed in several studies; the method has a low incidence of side effects and the patients solicit additional administrations; it is very simple only a single-shot administration in outpatients without any catheters or pumps; and finally, the costs of this method are very low. Indications and contraindications for spinal injections and an examination before injection in chronic pain patients are discussed in [20] with an emphasis on correlation between patient history, the type of pain, neurologic findings, and the results of an imaging examination. We try hard to proceed from simple interventions to sophisticated techniques. All of our patients undergo comprehensive medical management (CMM) for chronic LBP or FBSS (non-opioids, opioids, anticonvulsives, antidepressants, minimal invasive interventions trigger point injections or facet joint injections), and IT midazolam serves as a supplement to this therapy in the third stage of our algorithm (see Figure 1). The initial dose of 2 mg of IT midazolam was established on the basis of a comparative study [21] and one of the first clinical studies about the efficacy of spinal midazolam on somatic nociceptive pain [22]. The analgesic effect of intrathecally administered midazolam has been confirmed in a number of clinical studies, usually as a supplement together with an opioid and local anesthetics in postoperative analgesia, used mainly to strengthen the analgesia after a Cesarean delivery [23,24], abdominal surgery [25 27] or perianal surgery [10] but also in analgesic treatment for neuropathic or musculoskeletal pain as a continuous infusion with clonidine [28]. Better or longer lasting analgesia was achieved using a continuous IT infusion of midazolam in combination with an opioid, local anesthetics, or clonidine, with minimal drug-related side effects. Midazolam can be administered epidurally as well. Improved pain relief or an extended duration of analgesia with good cardiovascular stability after the addition of epidural midazolam was confirmed in postoperative analgesia after abdominal surgery in adults [29,30] or after inguinal herniotomy in children [31]. Early experience with single-shot midazolam in LBP patients was published by Serrao [21]. In this study, the authors compared the effect of intrathecally administered midazolam with that of epidural steroids and concluded that IT midazolam is an effective treatment for chronic LBP. In our department, we use midazolam as a third step in our algorithm in case epidural steroids have no or very little effect. The aforementioned comparative study [21] was the impulse for our clinical use of IT midazolam in patients with chronic LBP and for the development of our three-stage algorithm as well. Large meta-analysis from 13 studies confirmed perioperative analgesia and reduced nausea and vomiting after adding 1 to 3 mg of IT midazolam to other spinal medications without neurological symptoms [32]. Only morphine and ziconotide are approved for continuous intraspinal pain therapy according to the Polyanalgesic Consensus [33] and its actualized version in [34]; they constitute the first-level treatment for spinal analgesic infusion, whereas IT midazolam is level 5. However, opioids are not effective in all patients and are associated with many clinical limitations due to their numerous side effects (constipation, sweating, nausea, urinary retention, impotence, pruritus, etc.) [12]. Moreover, there are many reports of granuloma formation at the tip of a spinal catheter in animals [35] and in clinical studies [16,36]. Ziconotide in combination with opioids is an effective treatment option in cases in which all other pain therapy techniques have failed, but its wider use is limited by its frequent and severe adverse effects [37,38]. Usually, it is necessary to perform a slow titration and to use only submaximal doses [16]. Moreover, ziconotide needs to be administered as a continuous IT infusion. In addition, its cost is a great disadvantage as well. The neurotoxicity of spinally administered drugs used in pain therapy is reviewed in Hodgson et al. [39] and the neurotoxicity of spinal midazolam is still a controversial issue. One has to distinguish between histopathological (neural injury, gliosis, damage of the myelin sheath, inflammatory changes), physiological (changes of spinal cord blood flow, disruption of the blood brain barrier, changes in electrophysiology), and clinical changes (pain, motor and sensory deficits, bowel and bladder dysfunction, behavioral changes). Furthermore, many preservatives, antioxidants, or excipients used in drugs given spinally can cause neurotoxic changes in animal models even though they are safe when administered intravenously or intramuscularly [39,40]. The midazolam we use is solely preservative-free. There are some studies demonstrating histopathologic signs of neurotoxicity in some animal models (degeneration in myelin rings, vacuole formation, and edema in the cytoplasm), but these studies have generally used much higher doses of midazolam (0.12 to 0.6 mg/kg; see [41,42]). These neurotoxic effects are dosedependent, particularly in repetitive administrations [43]. In our patients, we used doses of 0.02 to 0.06 mg/kg and intervals between individual administrations of at least 4 weeks. Although we had 14 patients with

5 Intrathecal Midazolam for Chronic Back Pain administrations or more in our study, none of them displayed any clinical signs of neurotoxicity, such as bladder or bowel dysfunction, motor or sensory deficits, or new neuropathic pain. Our results are in conformity with the summary of another safety investigating study [44]. Complications might occur throughout the whole course of pain management. One should distinguish between procedure-related complications, device-related complications, and drug-related complications [45]. More complications may arise from an introduced spinal catheter: infection [45,46], granuloma formation particularly in the case of morphine [45], or PDPH [43]. Device-related complications associated with long-term spinal drug management are an issue in themselves: pump malfunction, catheter migration, occlusion, disconnection or displacement, inflammatory changes, the aforementioned granuloma formation, epidural or subarachnoid hemorrhage, and many others [36,47]. When no spinal catheter or delivery system is used but only a small-gauge spinal needle, these complications are not likely to appear. Some complications can also be found in the case of single injections: spinal hematoma, cauda equina syndrome, purulent meningitis, epidural abscess, traumatic cord lesions, paraparesis, etc. Their occurrence is, fortunately, extremely rare [48]. Occurrence of other complications in our study group was very low. As the most common side effect, we recorded drowsiness caused by sedative properties of midazolam. Spinal (IT or epidural) administration of midazolam is still regarded as off-label, specifically in the category of alternative route licensed product administration [49]. It is clear that the risks associated with off-label use represent a broad spectrum, the benefits of certain off-label uses may clearly outweigh the associated risks in certain patients, and off-label use plays a vital role in the practice and evolution of modern medicine [50]. The Food and Drug Administration (FDA) stated that once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations [51]. Moreover, these FDA regulations are intended only for the pharmaceutical industry; they do not cover medical practice proper [52]. Conclusion IT midazolam seems to be a suitable supplement to the CMM of patients with chronic LBP or FBSS who suffer somatic or neuropathic pain. Our study proved that analgesia was achieved for durations of 4 weeks or more following more than 60% of all administrations, with a low incidence of side effects. For clinical practice, it is strongly recommended to use preservative-free drugs only due to the potential neurotoxicity of additives. IT midazolam is still an off-label method; however, only wide clinical experience and laboratory research can convert it to on-label, similar to what happened with opioids some years ago. Until then, IT midazolam for pain relief should be used in strictly indicated cases. References 1 Cohen SP, Argof CE, Carrage EJ. Management of low back pain. BMJ 2008;38: Ragab A, deshazo RD. Management of back pain in patients with previous back surgery. Am J Med 2008;121(4): Chou R, Atlas SJ, Stanos SP. Nonsurgical interventional therapies for low back pain. Spine 2009;34(10): Manchikanti L, Boswell MV, Datta S, et al. Comprehensive review of therapeutic interventions in managing chronic spinal pain. Pain Physician 2009;12(4): E Manchikanti L, Boswell MV, Singh V, et al. Comprehensive evidence-based guidelines for interventional techniques in the management of chronic spinal pain. Pain Physician 2009;12(4): Conn A, Buonaventura RM, Datta S, Abdi S, Diwan S. Systematic review of caudal epidural injections in management of chronic low back pain. Pain Physician 2009;12(1): Parr AT, Diwan S, Abdi S. Lumbar interlaminar epidural injections in managing chronic low back and lower extremity pain: A systematic review. Pain Physician 2009;12(1): Goodchild CS. Nonopioid spinal analgesics: Animal experimentation and implications for clinical developments. Pain Rev 1997;4(1): Zeilhofer HU, Witschi R, Hösl K. Subtype-selective GABA A receptor mimetics Novel antihyperalgesic agents? J Mol Med 2009;87(5): Moore RA, Eccleston C, Derry S, et al. Evidence in chronic pain Establishing best practice in the reporting of systematic reviews. Pain 2010;150(3): Yegin A, Sanli S, Dosemeci L, et al. The analgesic and sedative effect of intrathecal midazolam in perianal surgery. Eur J Anaesthesiol 2004;21(8): Tucker AP, Mezzatesta J, Nadeson R, Goodchild CS. Intrathecal midazolam II: Combination with intrathecal fentanyl for labor pain. Anesth Analg 2004;98(6):

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