THE ADHESIVE ARACHNOIDITIS SYNDROME

TREATMENT OPTIONS

Generally speaking, this complex neurogenic pain syndrome is best treated at a specialist pain clinic, with a multidisciplinary approach.

Oral regimes:

Of the well-established treatment regimes, opiates are frequently used. However, these may be ineffective in combating any central component of the pain.

The issue of dependency concerns most practitioners and may lead to reluctance to prescribe. It is likely that there will be a risk of physical dependence, and thus of withdrawal symptoms if the opiate medication is discontinued. Also, there is an element of tolerance that may develop in long- term use, with the need for increasing doses for effective pain relief. However, psychological dependence and abuse are less likely in chronic pain patients than in those who use opiate drugs recreationally.

It is best to start with short-acting morphine four hourly, until adequate analgesia is established. Breakthrough pain may require top-up doses. Once control has been established, it is advisable to change to a slow release preparation such as MS Continus, which has a predictable duration of action for 8-12 hours, and can thus be given twice daily.

Oromorph and Oromorph SR have similar pharmacokinetics to MS Contin.

Fluctuations in dose requirement may occur, and in this case, the slow-release preparation should be replaced with a shorter acting one for the period of increased dose requirement.

There are new preparations such as Kapanol and Reliadol, which are modified-release formulations, which may be given once daily.

There are a variety of opioid drugs. Morphine remains the drug of choice. However, occasionally it may induce a paradoxical hyperpathia, which is resolved by substitution with an alternative opiate medication. ([60])

Other opiates include:

Methadone: which can be beneficial for neuropathic pain, but may have an unpredictable duration of action;

Pethidine has unwanted central effects and is too short acting;

Codeine is too weak and has constipating side effects.

Oxycodone: too short acting but suppositories may overcome this;

Dextropropoxyphene: a weak agonist, possibly metabolised to a cardiotoxic metabolite. (but a recent paper ([61]) has described it as an NMDA antagonist: see below)

Fentanyl: short-acting

There are also partial opiate agonists such as buprenorphine (Temgesic) which has a maximum analgesic dose equivalent to moderate doses of narcotics, but tend to cause less dependency.

Alternatively, Tramadol (Tramal/Ultram) is a synthetic centrally acting analgesic, which is unrelated to opiates and carries less risk of dependence. It is useful for moderate to severe pain and has few serious side effects. However, it should be used with caution in patients who are also taking CNS depressants.

McQuay ([62]) describes “Incident pain”, which may be brought on by activity, and is a major problem, as adequate background analgesia may be insufficient to control it. There may also be another type of incident pain, which is intermittent, and can occur at rest, without obvious trigger factors. It is very difficult to control.

Adjunctive treatment may be necessary to combat this type of pain:

Antidepressants are useful for the background burning neuropathic pain, but are used in far lower doses than for depression (e.g. amitriptyline 25mg at night). It should be noted that the more selective antidepressants such as Prozac have been found to be poorly effective against neuropathic pain, first generation tricyclics being much more useful.

Anticonvulsants such as carbamazepine are particularly useful for the sharp, lancinating type of neuropathic pain. A relatively new drug, Neurontin (Gabapentin) is useful for pain relief and muscle spasms.

A recent study in rats has shown that low-dose combinations of morphine, desipramine and serotonin can achieve good pain control. ([63]) The clinical application of this finding will only be possible after further studies have been undertaken.

Antiarrythmic drugs such as mexiletine (which is a local anaesthetic) may also be used for neuropathic pain.

Muscle relaxants may be needed, including benzodiazepines such as diazepam. For increased muscle tone (spasticity) baclofen is a useful drug.

Ketamine, an NMDA receptor antagonist, has been used successfully for neuropathic pain, especially in conjunction with opiates, when it may reduce the dose of opiate required.

Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen are not generally effective for pain relief and may cause significant gastrointestinal side effects and occasionally kidney problems after prolonged use.

Some patients have found that the troublesome nocturnal muscle cramps may be relieved by quinine.

Invasive treatments

These are not recommended by the Arachnoiditis Trust who believe that ANY invasive procedure carries a significant risk of exacerbating the inflammation of arachnoiditis, thereby worsening the patient’s condition.

However, as always, it must be a question of weighing up possible benefits against possible risks, and individual needs must be assessed.

INA (Intraspinal narcotic analgesia): the “pump”. This was originally developed for use in terminally ill cancer patients and thus was not being used long term. Of the studies of long term pump use, there are varying opinions as to its safety and efficacy. One recent paper states: “About one third of the patients get good long-term pain relief without

complications or side effects, many require the addition of local anesthetics, and some never get effective relief. There are major questions to be answered before this form of therapy becomes widely disseminated.”([64])

Opiates are often supplemented with either local anaesthetics such as bupivicaine, or antispasmodics such as baclofen.

Principal problems with perispinal drug therapy include system failure, infection and neurotoxicity. System malfunction varies according to manufacturer, but tends to run at about 20%([65]). There are a number of papers documenting cases in which intrathecal granulomatous tissue has formed at the pump site. ([66]) Bearing in mind that this is a form of scar tissue, this has special relevance to arachnoiditis patients who already have scarring problems.

A further paper ([67]) describes evidence of focal subdural fibrosis and discrete injuries to nerve roots in patients with intrathecal infusions of morphine and bupivicaine.

The neurotoxicity of intrathecal drugs is mostly related to the preservatives used in the solutions. Baclofen for intrathecal injection is preservative free, but anaesthetic agents are usually in solutions containing preservatives. The FDA has cleared the use of preservative free morphine sulfate and baclofen, for pump use. Usually the injectable form of morphine sulfate contains 0.5% chlorobutanol (a derivative of chloroform) and not more than 1% sodium bisulfate in every ml of morphine sulfate injection USP. An animal study in 1993 showed that 0.05% chlorobutanol injected intrathecally “induced significant severe spinal cord lesions” ([68]) It is therefore vital to ensure that preservative

free solution is used. Chlorobutanol toxicity may cause increased somnolence, alterations in speech patterns, dysarthria and haemodynamic changes. ([69])

A study on the neurotoxicity of intrathecal agents ([70]) suggests that complications may occur in patients after high doses of morphine. These were related to one of its metabolites, morphine-3-glucuronide.

Adverse effects of INA such as constipation, nausea, vomiting and itching tend to be short-term, whereas loss of libido and potency may persist for several months. The most persistent side-effects are sweating and oedema (swelling), the latter of which may necessitate INA being discontinued. The most serious adverse effect is respiratory depression

Spinal Cord Electrostimulation (SCS) involves electrical stimulation by implanted electrodes around the spinal cord. (in the epidural space), in the area that is most involved in causing pain. The very low energy current shuts down the input of pain fibres. Success rates seem to vary in different studies but are overall approximately 50% when all types of chronic pain are considered, and the benefits may decrease with time. However, there is little literature on its efficacy in the specific case of arachnoiditis. Kumar ([71]) suggests that there is a favourable response to treatment of postsurgical arachnoiditis or perineural fibrosis if the pain is predominantly confined to one lower extremity. Meilman et al ([72]) also state that SCS is of greater efficacy for unilateral lower limb pain than for more widespread nerve root involvement. It is best for controlling the dull, constant pain and poor for the sharp, lancinating pain. SCS may also be useful for neurogenic bladder problems. ([73])

Complications include wound infection, electrode displacement and fibrosis at the tip of the stimulating electrode. ([74]) The latter is, of course, of concern as regards the potential problems specific to arachnoiditis patients.

Surgical treatment is generally regarded to have a low success rate. Resection of scar tissue is often followed by recurrence. Some specialists are now using laser techniques, but data on the outcomes is limited.

Epidural steroid and local anaesthetic injections: as previously detailed, these are of questionable (and temporary) benefit and carry a risk of causing the very problem they are being used to treat. O’Connor et al ([75]) sum up the situation by stating that the “abnormalities of the epidural and subarachnoid spaces in such patients”(i.e. with chronic spinal arachnoiditis)… gives rise to “unpredictable and potentially dangerous results” following drug injection into these spaces.

Local nerve blocks

For those patients who have been diagnosed with RSD, sympathetic blockade may be offered. However, the literature is divided as to the efficacy of these techniques. Whilst they may be of use in the initial phases of the condition, when sympathetically maintained pain (SMP) is predominant, once central sensitization occurs (and thence what is termed “sympathetically independent pain: SIP”) they are much less likely to be effective.

Other modes of administration

These include transdermal patches e.g. clonidine (an antihypertensive agent, may therefore cause drop in blood pressure) fentanyl (an opiate agonist). Fentanyl patches tend to produce fewer side effects than oral morphine.

The FDA has recently approved a new innovation: Actiq is a crystallized form of fentanyl that comes in lozenges for buccal use (put inside the cheek, where it is absorbed rapidly into the bloodstream). This mode of administration allows almost immediate relief from intense flare-ups of pain. It is used in treatment of cancer patients at present.

Ketamine nasal spray is available in the USA. This needs to be investigated further.

Topical application of capsaicin is used to treat pain in peripheral neuropathies such as seen in diabetes mellitus. However, contact with the support group COFWA suggests that many patients find the initial (expected) increase in pain (which occurs prior to the anaesthetic effect) is intolerable, and few remain using it.

Non-pharmacological treatments

These include:

Transcutaneous Electrical Nerve Stimulation: TENS (of limited use)

Acupuncture (contact with patients who have tried this suggests that it is not as useful as could be hoped)

Physiotherapy: must be gentle as vigorous exercise may precipitate a flare-up. As in PPS, a non-fatiguing programme is likely to be the most beneficial.

Hydrotherapy: often very useful, but the water must not be too warm (heat intolerance is common in arachnoiditis patients)

Hypnosis

Biofeedback

Cognitive techniques

Relaxation/meditation: these are all helpful adjuncts to drug treatment, but few patients can manage on these pain management techniques solely.

3 relatively new techniques are becoming available:

1.APS (Action Potential Simulation) electrical stimulation (non-invasive) similar to TENS but of a different electrical waveform.

2.LLLT (Low-level Laser Therapy) again, non-invasive, resembling ultrasonic treatment in its application, it has been used with success in patients with various types of neuropathic pain, (e.g. post-herpetic) but mostly in more localized conditions.

3.PENS (Percutaneous Electrical Nerve Stimulation) is a technique that bridges acupuncture and electrical stimulation (TENS); low level electrical current (cf. TENS) is delivered via a series of ultra-fine, acupuncture-like needles. A recent study ([76]) has demonstrated that PENS was more effective than TENS in providing short-term pain relief and improved physical function in patients with chronic low back pain.

Motor-level electrical stimulation has been used for management of chronic pain with muscular involvement. Wheeler et al ([77]) describe its use for spinal rehabilitation. There are multiple beneficial effects; some degree of pain relief, interruption of the pain-spasm cycle (and thus reduced myospasm) increased blood flow to muscles, muscle strengthening and neuromuscular re-education. The Wheeler study showed that patients

with chronic neck or low back pain with a muscular component, benefited from the treatment, although patients with an inflammatory disorder were excluded from the study. The possibility of this form of treatment being beneficial to arachnoiditis patients needs further investigation.

Experimental treatments

NMDA receptor antagonists such as dextromethorphan. (NMDA receptors are implicated in the “wind-up” mechanism of spinal sensitization). They look promising for neuropathic pain, but a recent study has shown that dextromethorphan (DM), a widely used non-prescription antitussive (cough medicine) may be teratogenic, causing foetal abnormalities in chicken embryos ([78]). At this time, I would advise against the use of this drug in pregnant women, until further evidence is put forward. It is of some use in reducing morphine tolerance.

MorphiDex has been developed by Algos. This drug combines DM with morphine, thereby increasing the effectiveness of the narcotic without increasing side effects. It is under application to the FDA.

Memantine is another NMDA antagonist undergoing trials.

Ziconotide (SNX-111) is an experimental drug that shows promise for future use, but further extensive trials will be needed before it reaches clinical use.

ABT-594 is another drug in trials, based on a toxin found in the skin of frogs. This has been found to be 50 times as effective as morphine in animals.