In our final science article for 2012 on pharmaceutics, Kalliopi Dodou takes a look at the less commonly used intrathecal route of drug delivery
Intrathecal and epidural drug delivery comprise the intraspinal routes of drug administration. Each route delivers drug to the cerebrospinal fluid (CSF). Intrathecal delivery involves the direct injection of the drug into the CSF within the intrathecal space of the spinal column, whereas drugs injected in the epidural space have to cross the dura membrane in order to reach the CSF. As such, epidurally administered drugs can also reach the systemic circulation whereas intrathecally administered drugs are confined within the CSF circulating in the spinal column and the brain ventricles.1
Intraspinal drug delivery emerged in the 1970s when the presence of opioid receptors in the spinal cord was discovered and has since been exploited for the treatment of persistent pain in patients who do not respond to or experience serious side effects to other analgesic formulations. The intrathecal route allows direct drug administration to the CSF by circumventing the blood-brain barrier. It therefore allows delivery of smaller drug doses and the occurrence of side effects is reduced compared with systemic routes of drug administration (eg, oral, intravenous and epidural).
Intrathecal drug delivery is currently approved in the UK for:
• The treatment of chronic spasticity due to injury, multiple sclerosis and cerebral palsy (eg, intrathecal baclofen injection/infusion)
• The management of cancer, chronic non-malignant or neuropathic pain (eg, intrathecal morphine)
• Chemotherapy treatment for lymphomatous meningitis (eg, methotrexate, cytarabine)
• Antibiotic treatment adjuvant to systemic antibiotic therapy in bacterial meningitis and other infections of the central nervous system (eg, gentamicin intrathecal injection)
Formulation principles and challenges
Intrathecal formulations are sterile isotonic drug solutions. The volume of intrathecal injections ranges from 0.5ml to 5ml. Drug solubility in such a small volume can be a challenge for lipophilic agents. Conversion of drugs to their water soluble salts (eg, gentamicin sulphate) or use of buffers can enhance solubility.
The CSF is a clear sterile aqueous liquid with no immune defence mechanisms (white blood cell count is between 0 to 5) and its protein and glucose content can render it an ideal environment for bacterial growth.2 So it is imperative that intrathecal formulations are free from micro-organisms. Aseptic techniques are used for the preparation and assembly of intrathecal injections and the drug solution is filtered using a 0.2µm filter. Also, intrathecal formulations must be preservative-free. Studies have shown that preservatives such as parabens and benzyl alcohol can cause inflammation of the arachnoid membrane (arachnoiditis) and nerve damage. Neurotoxicity is the main side effect of intrathecal drug delivery arising from unsuitable excipients, buffers, solubility enhancers and even the active drug itself. Ideally, intrathecal formulations should contain as few excipients as possible and the active drug must be screened for its propensity to cause neurotoxicity.
Surgically fitted intrathecal pumps are suitable for chronic intrathecal drug delivery (eg, analgesia and chemotherapy). Pumps can be externally fitted with a percutaneous or totally implanted catheter, or can be fully implanted systems.3
The Department of Health has issued a report to the chief medical officer on the prevention of intrathecal medication errors, acknowledging their significance and raising awareness among healthcare professionals.4 It is emphasised that intrathecal drug administration is a specialised skill and it must therefore be carried out by appropriately trained staff according to hospital procedures and protocols. Medication errors can be irreversible and fatal. A profound example is the intrathecal injection of intravenous vinca alkaloid drugs (eg, vincristine), resulting in severe neurological damage and death.
Therapeutic uses and future prospects
Intrathecal chemotherapy
Intrathecal administration of chemotherapeutic agents is useful in certain types of cancers that are found in the CSF (eg, CNS leukaemia and lymphoma) and for the prevention of cancer metastasis to the CSF.
Optimum chemotherapy requires sustained cytotoxic drug levels in the CSF. Because of the short half-life of cytotoxic agents (methotrexate and cytarabine), frequent intrathecal injections (lumbar punctures) are necessary, which are painful and inconvenient for the patient. In addition, drugs with a short half-life do not circulate long enough in the CSF to allow good distribution throughout the neuraxis, resulting in suboptimal therapeutic effect. Sustained release intrathecal formulations have therefore been designed in order to reduce dosage frequency and increase patient compliance, and ultimately to improve therapeutic outcome by allowing better drug distribution along the neuraxis.
Implantable pumps offer continuous drug release but, because they require surgery, they can be inconvenient and also carry the risk of post-operative infection.
Another approach is the single intrathecal injection of extended release lipid-based formulations. Studies on a rat model using a lipid-based formulation of methotrexate for neoplastic meningitis showed 18-fold increase (from seven hours to five days) in its half-life in the CSF.5
DepoCyte is a commercial lipid-based intrathecal formulation containing cytarabine, using the DepoFoam technology. It involves lipid microcapsules (3–30µm in diameter) filled with an isotonic (sodium chloride 0.9 per cent w/v) aqueous suspension of cytarabine. After a single injection of DepoCyte, cytotoxic concentrations in the CSF can be maintained for over 14 days in contrast to conventional cytarabine intrathecal injections that require administration two to three times per week.6
Intrathecal antibiotic therapy
Intrathecal antibiotic delivery is ideal in cases of CSF infection (eg, meningitis) that require direct and prompt antibiotic therapy. A study on neonates with pyogenic meningitis highlighted the importance of delivering antibiotics directly to the CSF either via lumbar puncture or intraventricular injection. The study concluded that, in severe cases, direct antibiotic delivery in the CSF of the brain ventricles was required to improve survival rates.7
Intrathecal analgesia
Despite the risks involved in intrathecal administration, the British Pain Society has stated that intrathecal drug delivery is underused and that it should be made more widely available for the management of chronic non-malignant pain, cancer pain and spasticity.
This claim is supported by studies showing improved quality of life and increased longevity in cancer patients receiving intrathecal opioid analgesia mainly due to a reduction in systemic side effects. There is also a suggestion that systemic morphine administration inhibits the immune system therefore compromising survival in cancer patients compared with intrathecally delivered morphine, which does not seem to exert the same immunosuppressive effect.8
Combinations of intrathecal analgesics are also used in clinical practice, for example, morphine sulphate mixed with bupivacaine hydrochloride and clonidine hydrochloride.9
Several compounds have been studied as intrathecal analgesics. Clonidine, an alpha-2 agonist, has shown effectiveness in neuropathic pain, complex regional pain and cancer pain when administered intrathecally, either alone or in combination with opioid analgesics.9 Gabapentin has recently been patented as an intrathecal analgesic for the management of neuropathic pain.
A study at Buffalo University, US, showed that the use of a surgical intrathecal pump delivering narcotic medicines provided effective analgesia to patients with post-herpetic neuralgia caused by shingles who did not respond to oral medicines. The study involved five patients with a mean age of 75 years. None of the patients experienced complications and all patients demonstrated improved pain relief.10
Intrathecal analgesia is also used in labour as an alternative to epidural analgesia to provide quick onset pain relief. The advantage of intrathecal analgesia is that it does not slow the progress of labour and improves the chances of vaginal rather than caesarean delivery.11
Protein delivery to the CNS
Protein delivery to the CNS can be useful to treat genetic diseases. Intravenous administration, however, is challenging because proteins do not cross the blood brain barrier at sufficient levels to exert a therapeutic effect. Intrathecal delivery is therefore being investigated as an alternative route for enzyme replacement therapies. A current phase I/II clinical trial is examining the intrathecal delivery of idursulfase, an enzyme that is absent or deficient in patients with Hunter Syndrome.12
Diagnostic tool
Intrathecal extraction and examination of CSF can be used as a diagnostic tool for CNS infections and other disorders. For example, elevated levels of immunoglobulin in the CSF can be an indicator of multiple sclerosis.2
Conclusion
Despite the risks involved, intrathecal administration can improve the quality of life of patients with chronic persistent pain.
Intrathecal antibiotic treatment can be life-saving in CNS infections and, as current clinical trials expect to demonstrate, intrathecal enzyme delivery may provide hope to patients with incurable genetic conditions.
References
1 Intrathecal drug delivery in chronic pain. Available at: functionalneurosurgery.net (accessed 12 October 2012).
2 Medline Plus. CSF cell count. Available at: www.nlm.nih.gov (accessed 12 October 2012).
3 Department of Health. Updated national guidance on the safe administration of intrathecal chemotherapy. August 2008. Available at: www.dh.gov.uk (accessed 8 October 2012).
4 Department of Health. The prevention of intrathecal medication errors. April 2001. Available at: www.dh.gov.uk (accessed 8 October 2012).
5 Chatelut E, Kim T, Kim S. A slow-release methotrexate formulation for intrathecal chemotherapy. Cancer Chemotherapy and Pharmacology 1993;32:179–82.
6 DepoCyte product monograph. Available at: www.napponcology.co.uk (accessed 8 October 2012).
7 Yeung CY. Intrathecal antibiotic therapy for neonatal meningitis. Archives of Disease in Childhood 1976;51:686–90.
8 The British Pain Society. Intrathecal drug delivery for the management of pain and spasticity in adults; recommendations for best clinical practice. August 2008. Available at: www.britishpainsociety.org (accessed 8 October 2012).
9 Smith HS, Deer TR, Staats PS et al. Intrathecal drug delivery. Pain Physician 2008;11:S89–S104.
10 American Association of Neurological Surgeons. Intrathecal medication therapy effective for painful post-herpetic neuralgia caused by shingles. Medical News Today, May 2009. Available at: www.medicalnewstoday.
com (accessed 8 October 2012).
11 Minty RG, Kelly L, Minty A et al. Single-dose intrathecal analgesia to control labour pain. Canadian Family Physician 2007;53:437–42.
12 A safety and dose ranging study of idursulfase (intrathecal) administration via an intrathecal drug delivery device in pediatric patients with Hunter Syndrome who have central nervous system involvement and are receiving treatment with Elaprase. Available at: www.clinicaltrials.gov (accessed 8 October 2012).
Kalliopi Dodou is senior lecturer in pharmaceutics in the Department of Pharmacy, University of Sunderland
