Intraspinal drug delivery systems, sometimes referred to as "the pump" are implanted therapy for drug infusion, commonly using opiates.

Selection criteria for pump implantation include:

1. Chronic intractable pain that has failed to respond to less invasive methods of pain control.

2. Systemic (oral, rectal, intravenous) analgesics cause intolerable side effects

3. Good to excellent pain relief from test dosing

4. Patient is not allergic to morphine

To ensure that the technique will be successful a preimplantation screening is necessary. This may involve bolus injections or a continuous epidural infusion over 2-3 days.

Implantation can be performed under local anaesthesia or regional blockade and patients may be discharged 2-3 days later. Initial intrathecal doses are calculated from the epidural doses necessary to provide good pain relief, at a ratio of a tenth the epidural dose and can continue to be increased/decreased as required after discharge.

The pump is activated at the time of implantation. The pump reservoir holds approximately 30-90 days' worth of medication, refill being done at intervals depending on pump delivery rate (usually every 25-50 days) Refill can be easily done by a nurse in an outpatient setting and takes up to half an hour.

IMPORTANT WARNING:

MRI scanning will temporarily stop the rotor of the pump and prevent delivery of the drug for the duration of the scan. There may also be possible temperature rises in the tissue around the pump: the FDA guidance permits a rise of up to 2 degrees centigrade.

Pumps such as Synchromed contain ferromagnetic components that will cause image distortion and image dropout in areas around it. However, the effect of this can be minimised by careful choice of pulse sequence parameters and location of the angle and imaging plane.

Morphine is the standard drug used in intraspinal analgesia.

Opioid Epidural dose Duration

Morphine 5-10mg 6-24 hrs.

OTHER DRUGS USED IN THE PUMP:

1.BACLOFEN: to combat muscle spasms; preservative free preparation is the only one approved by the FDA.

2.CLONIDINE (Duraclon): licensed for epidural use but NOT intrathecal!

3. BUPIVICAINE (a local anaesthetic): may contain neurotoxic preservatives

4.KETAMINE : some preparations contain chlorbutanol, a neurotoxic preservative

COMPLICATIONS:

• variable delivery rate

• catheter becomes disconnected

• CSF(cerebrospinal fluid) leak

• Catheter displaced from epidural or intrathecal space

• Catheter occluded

• Catheter kinked

• Ligature around the catheter

• Fibrotic encapsulation of catheter (renders drug delivery ineffective and may produce neural compromise by mass effect)

• Pump pocket infection

• Surgical wound dehiscence

• Bleeding/haematoma (collection of blood)

• Pocket seroma (collection of fluid around the implant)

• Battery depletion

• Component failure

• Procedural complications

Other adverse events outlined by Medtronics (manufacturer of Synchromed) include:

• Spinal headache

• Epidural abscess

• Meningitis

• Arachnoiditis !!

• Drug toxicity : hyperalgesia syndrome*

*A painful dose-limiting toxicity often of unexpected acute onset : severe pain, hypersensitivity, autonomic abnormalities, myoclonus. It is dose-related and tends to occur at high doses of intraspinal opiates. (may be related to M-3-G metabolite accumulation) This may be termed "paradoxical pain" and may be reduced by decreasing the opiate dose (plus systemic administration of benzodiazepine if necessary).

Side-effects of the pump include:

• Constipation

• Nausea and vomiting

• Itching

• Oedema

• Sweating

• Loss of libido

• Impotence

• Urinary retention

• Cessation of menstruation

• Nightmares

• Anxiety states

The majority of these side effects subside within a couple of months, the most persistent tending to be constipation, sweating and swelling, which may necessitate discontinuing this form of treatment.

A well-known study by Winkelmuller() showed that most patients started at about 1.6mg to 3mg of morphine daily and over a 6 month period their doses increased by between 60 and 100%. It was predicted that some patients were likely to require further dose escalation over the coming months and years.

SCS may be used to treat patients with Failed Back Surgery Syndrome, arachnoiditis, neuropathic limb pain, phantom limb pain, Reflex Sympathetic Dystrophy (RSD or CRPS: Complex Regional Pain Syndrome) It may also be used in intractable angina and peripheral vascular disease.

Spinal Cord Stimulation or SCS is a technique involving electrical stimulation of a precise part of the spinal cord. A very low energy current is used. This essentially shuts down the pain signals from the part of the body served by that area in the spinal cord. Whilst providing pain relief, other sensory input is not affected and there is normal motor(muscular) function. Basically, the theory behind SCS is that sending non-painful signals will block out the painful ones: in much the same way as we instinctively rub our hand if we have banged it.

Instead of feeling pain, the patient will experience tingling.

RESULTS WITH SCS:

The Pain Management Center of the University of Utah Hospitals and Clinics website ( )reports less than encouraging figures:

"Outcome:

1. 55% report initial relief

2. Relief after 6 months 33%

3. Relief after 2 years 12%

4. Relief after 10 years 5%"

ADVERSE EFFECTS OF SCS:

These include:

• infection

• bleeding, hemorrhage

• headache

• hardware difficulties

• spinal cord injury

• allergic reactions

• failure to relieve pain

• paralysis

• haematoma

• pain at implant site

General complications with the system :

• no stimulation or intermittent stimulation

• stimulation in the wrong location

• loss of pain relieving effect

allergic response to system

IMPORTANT NOTE:

Anti-theft and metal detector systems may affect spinal cord stimulators, due to the effect of their electromagnetic fields. These security systems may cause overstimulation, and patients will report pain, jolts and shocks.

Epidural steroid injections are often offered to patients who have intractable back pain, including those who have Failed Back Surgery Syndrome.

However, there is plenty of evidence that ESIs are poorly effective for this purpose and moreover carry significant risks of worsening the patient's condition, especially if there is a pre-existing spinal problem, which given the population of patients involved is in the majority of cases.

Depo-Medrol (Depomedrone) is a steroid preparation administered epidurally or intrathecally in the treatment of acute back problems as well as Failed Back Surgery Syndrome (FBSS).

The rationale for its use is that the steroid (methylprednisolone) is an anti-inflammatory agent, which is aimed at reducing nerve root inflammation that may be caused by a variety of problems such as a prolapsed disc. Although in itself beneficial, the drug is in a solution that contains preservatives such as polyethylene glycol (also used in antifreeze). Other preparations such as Kenalog use benzyl alcohol. It should be noted that alcohol is a recognised cause of toxic neuropathy, so adverse reactions are unsurprising.

BENEFITS?

McQuay() cites an NNT (number needed to treat one patient successfully) of 7.3 for greater than 75% pain relief in the short term(1-60 days) and 13 for more than 50% pain relief in the long term (12 weeks to 1 year). In comparison to adjuvant analgesics such as antidepressants and anticonvulsants which have NNTs of between 2 and 3 for intractable neuropathic pain, ESIs are patently much less effective.

RISKS

Since the withdrawal of oil-based myelography, Depo-Medrol is the principal cause of adhesive arachnoiditis in the Western world. Adhesive arachnoiditis is an incurable neurological condition that causes severe intractable back and limb pain as well as a wide range of other debilitating symptoms. Dr. Burton of the Institute of Low Back and Neck Care in Minnesota, maintains that almost all cases of clinically significant adhesive arachnoiditis are caused by Depo-Medrol:

"NOTE: Over the past decade, following the cessation of use of oil-based myelographic agents in the 1980s, the most common cause of incapacitating, clinically significant, adhesive arachnoiditis in the world population has now become the subarachnoid deposition of substances containing polyethylene glycol."() He also now recognises that other steroid preparations such as Aristocort (Kenacort) or indeed any preparation which contains neurotoxic preservatives may also be causative factors.

Furthermore, if there are multiple injections are given, the risks are higher.

The debate on the neurotoxicity of ESIs has centred on the notion that the epidural space is a great deal more forgiving than the subarachnoid (intrathecal) space and that intrathecal damage seen in animal studies is irrelevant as epidural injections do not reach the subarachnoid space. However, this completely fails to take into account the use of epidural anaesthetics, which are by design given precisely because they get through to the subarachnoid space and exert their intended effect on the spinal cord. Indeed, it is widely accepted as part of clinical practice that epidural doses need to be about 10 times higher than intrathecal as only 10% of the dose will reach the subarachnoid space. In other words, this admits that 10% of epidural steroid injections could reach the subarachnoid space.

Depo-medrone (depo-medrol) is the most widely used preparation but a substantial minority of cases involve the use of Kenalog/Adcortyl/Lederspan, which all contain preservatives such as benzyl alcohol or polyethylene glycol. Most of the manufacturers clearly state in the information about the product that it is not recommended for epidural use. Nor are these preparations licensed for epidural use.

The only steroid preparation in the UK that does not contain preservatives is Decadron manufactured by Faulding.

THE TIRANTI CASE On February 3, 2000, a 38year old woman in New Jersey ,USA was awarded $12 million as compensation for arachnoiditis which developed as a result of depo-medrol (depo-medrone) injected into the subarachnoid space in 1986. The size of the award was in compensation for her past and future disability as well as her pain and suffering.

Steroids are not licensed for epidural use and the manufacturers state that they do not recommend their preparations for use around the spine.

One of the problems in assessing the level of risk of ESIs as regards causing long- term adverse effects, is that virtually all the medical literature pertains to short-term studies which will not pick up conditions such as arachnoiditis. This leads to a vicious circle: Under-researched>> Perceived as RARE>> Not recognised>> Under-diagnosed>> Under-reported ADRs*

*adverse drug reactions

The Arachnoiditis Trust are in discussion with the Department of Health on the issue of Epidural Steroid injections: we have been informed that the DOH are running a study on the efficacy of ESIs results of which will be available in 2003. In the meantime, the Trust will continue to work towards this form of treatment being discontinued, and will be informing the public of the risks inherent in it, as a measure to prevent further cases: one cannot use the adage "prevention is better than cure" because there IS no cure for arachnoiditis...prevention is the only option available at this time to make some headway in a condition which is by no means as rare as clinicians seem to believe.

Epidurolysis is used to dissolve scar tissue around trapped nerves in the epidural space: i.e. it reduces the amount of epidural fibrosis. It was pioneered by Dr. Gabor Racz.

Scarring (adhesions) in the epidural (peridural/extradural) space is common after spinal surgery. It may be severe and cause symptomatic compression of nerve roots as they exit the spinal cord.

The epidurolysis involves injection of a mixture of local anaesthetic (lidocaine/bupivicaine) , steroid (triamcinolone: Aristocort/Kenalog; methylprednisolone: depo-medrol/depo-medrone), X-ray contrast agent, the enzyme hyaluronidase(hyalase) and concentrated salt solution.

Hyaluronidase is a naturally occurring enzyme which acts on hyaluronic acid, which is the "glue" that binds connective tissues together.

The procedure involves an injection of contrast agent into the epidural space in order to locate the scar tissue. Then an implanted catheter is used to deliver hyaluronidase safely and also to perform some mechanical lysis of the scar tissue.

You will note that the other components of the injectate are already familiar to us from looking at epidural steroid injections. Of course, exactly the same risks pertain to the use of these substances in epidurolysis as to their use in ESIs.

Furthermore, the various types of attempts to reduce scar tissue, including endoscopic resection, will at best only have short term benefit as the scar tissue tends to recur. In fact, these procedures may exacerbate the problem considerably and of course a procedure such as Racz, which uses such a toxic cocktail of injected agents carries a risk of causing arachnoiditis.

Nerve blocks have been used for relief of intractable pain for many years, and also for relief of spasticity (rigidity of muscles, perhaps with muscle spasms) for over 30 years.

Nerve blocks may be diagnostic, therapeutic, or both. Diagnostic block last a matter of hours to a couple of days, whereas therapeutic blocks may last 8-12 weeks or possibly if permanent nerve ablation is performed, for several years (it is not completely permanent).

It is well recognised that even when performed by very experienced clinicians, diagnostic nerve blocks have limitations in the accuracy of their results: false-negative and false-positives are not uncommon occurrences.

The basic premise of the diagnostic nerve block is to inject a non-irritant solution of local anaesthetic into the nerve or nerve plexus (a collection of nerves e.g. the brachial plexus in the armpit) suspected of being involved with the pain experienced by the patient. This injection is done to see if the patient's symptoms can be reproduced by it, and then pain relief is achieved following administration of sufficient local anaesthetic to give a temporary nerve block.

PERMANENT NERVE BLOCKS:

Ethanol (alcohol) has been widely used in neurolytic procedures. Concentrations from 3-100% may be used. It destroys nerves by extracting cholesterol and other lipids(fats) and by protein precipitation. However, axonal regeneration is possible (unless the cell body is destroyed). High concentrations of alcohol (90-100%) may produce a chemical neuritis.

Phenol: Animal studies show that phenol (carbolic acid) at 6% concentration causes local necrosis in 24 hours, complete degeneration by 45 days and regeneration in 75 days. Sensory recovery after phenol is faster than after alcohol.

NOTE: Chemical neurolysis does NOT effect a permanent nerve block (SEE BELOW)

WHY "PERMANENT" NERVE BLOCKS ARE NOT PERMANENT:

Up until recently, it was thought that the nervous system was incapable of regeneration. However, nowadays, it is well recognised that the nervous system has quite remarkable "plasticity" (ability to change).

This explains why some patients treated with nerve blocks or nerve ablation fail to gain any relief from their pain and indeed, some may experience worse pain.

Permanent nerve blockade has been established using phenol, which basically kills off most of the nerve, thereby interrupting the pain message pathway. However, it is now known that the axon (main part of the nerve) responds to this by putting out "sprouts" which tend to come from the side of the axon as opposed to the end of it. These sprouts can transmit severe pain.

Also, if chemical neurolysis is performed using either alcohol or phenol, there may be tissue damage to these noxious chemicals in the area around the nerve block. This damage may well result in scar tissue formation which itself can become a source of pain.

This technique of using phenol to block nerves is called neurolysis or nerve ablation. It is also used to treat peripheral nerves that have been injured (e.g. brachial plexus avulsion) or painful peripheral neuropathy, as well as nerve pain in cancer.

Even temporary nerve blocks using local anaesthetics (with or without a steroid) can cause significant problems; for example, pain may develop in the areas of skin served by the nerve that has been injected; this occurs mostly if the nerve involved has both sensory and motor functions. It may last for weeks; some clinicians then treat this new problem with a further nerve block, which may well make matters worse still rather than ameliorating them.

There is a new innovation to effect neurolysis: Radiofrequency Neurolysis(Ablation)(RF)

RF uses radiofrequency waves to shake up charged chemical particles (ions) within the nerves, thus producing heat, which is allowed to reach approximately twice the body temperature for 60-90 seconds. This technique appears to produce a longer-lasting pain relief than chemical nerve blockade, and there is not the risk of spread of the chemical.

Dr. Gatell of the Atlanta Pain Relief Centre has used this technique. He warns "however, each individual case may not resond with 100% pain relief, and pain may recur or even become worse (Anesthesia Dolorosa).So RF is best reserved as a last resort in treating intractable chronic painful conditions that have not responded to optimal medical pain therapy."

SUMMARY: nerve blocks are never permanent and may result in worse pain: they should be reserved for patients with a terminal illness.

Intrinsic disc mediated pain (IDP) is pain which arises from a non-prolapsed disc but one which may have internal disruptions to its structure such as an annular tear, which can allow irritant disc contents to leak out and cause inflammation in nearby nerve roots. Epidural steroid injections (ESIs as described above) are one form of treatment, but may not reach the target nerve roots. Intradiscal neurolytics (such as phenol) have been used in an attempt to damage the nociceptive fibres in the annulus of the disc. 7% phenol solutions or high concentration anaesthetics such as 10-15% lidocaine have been injected. However, there are very considerable safety concerns over epidural or intrathecal spread of the injectate and subsequent damage to nerve roots or even the spinal cord by these highly toxic substances.

Chymopapain, an enzyme that has been used for chemonucleosis in treatment of prolapsed discs, also has been implicated in causing epidural fibrosis and animal studies show severe nerve damage if injected into the nerve sheath.

Intradiscal radiofrequency ablation has the same aim . There have been some studies done on this.

There are still some major questions to answer about this therapy.

However, there is now a new similar therapy called IDET: intradiscal electrothermal therapy. It essentially does what RF attempts to do, but uses an electrical source of heat to thermocoagulate the annular nerve endings. It basically does 3 things:

• Destroy pain receptors in the disc

• Change the structure of the disc material

• Cauterise new pain receptor nerve fibres and blood vessels that have grown into the degenerative disc.

IDET has the advantage over chemical neurolysis in that it affects the relevant disc exclusively and does not damage surrounding tissue. However, as discography is far from infallible, the success of this procedure is partly dependent on treating the source of the patient's pain. This may be relatively uncomplicated in acute problems if the patient has never has previous back problems. However, anyone with chronic problems, especially those with Failed Back Surgery Syndrome will inevitably have pain from various sources. Indeed, if there is epidural fibrosis or arachnoiditis, this will also complicate the accurate placement of the IDET cannula inside the disc.

Patients who are likely to benefit are those with well- circumscribed symptoms attributable to a disc(or possibly discs) that can be demonstrated on MRI to have internal structural disruption or a small degree of contained herniation(prolapse). These patients will not have neurological signs on clinical examination.

Those who are unlikely to benefit include patients with nerve compression, stenosis, significant disc herniation, or pain from multiple anatomical sources.

I would certainly NOT recommend this form of therapy for anyone with chronic spinal problems.

These are well established treatments for pain due to Myofascial syndrome or fibromyalgia, but they have little real therapeutic value, especially as these syndromes tend to be associated with underlying musculoskeletal structural problems. They are indicated in those patients who have consistent well-circumscribed trigger points which elicit their painful symptoms. These must have been consistently observed and documented as the typical local twitch response, characteristic pain radiation and local autonomic reaction. The injections are not indicated unless the clinically significant trigger points (i.e. those related to the troublesome symptoms) have failed to respond to more non-invasive techniques such as vapocoolant spray and stretch, ischaemic pressure massage (myotherapy), specific soft tissue mobilisation and hot packs.

Some doctors perform "dry needling" in which there is no medication injected. Injected medication is either lidocaine(a local anaesthetic), or lidocaine combined with a steroid. (see Epidural steroid injections.)

Adverse events include (rarely): infection; pneumothorax(air in the chest cavity), anaphylaxis (severe allergic response) penetration of viscera (e.g. gut), neuropraxia and neuropathy (damage to nerves).

After injection, muscles should not be vigorously exercised until soreness has subsided. However, stretching of the affected muscles is recommended by practitioners of this procedure.

DURATION: OPTIMUM: 4 weeks, Maximum 8 weeks

SUMMARY: Trigger point injections are invasive and may potentially cause serious adverse effects; patients who have myofascial symptoms secondary to a spinal condition or other underlying cause should have this investigated and treated first before trigger point injections are undertaken.

DREZ means dorsal root entry zone lesions which are used to combat intractable pain. DREZ is a type of neurolytic surgery. (the other types are beyond the scope of this article). Quite an extensive spinal surgery is needed to perform this procedure, and it is common for it to cause dysesthesias(bizarre painful sensations) ataxia (unsteady gait) and/or weakness.

The use of DREZ does seem to effect a good degree of relief of neuropathic pain that has previously been resistant to treatment. However, it is quite clear from the published literature that there may be serious risks attached to this procedure. It seems therefore best reserved for patients whose overall condition, especially neurologically speaking, is sufficiently poor that the more serious adverse effects are still acceptable within the context of the relief and possible improvement in quality of life. It does not seem to be in any way suitable for patients who have relatively minor neurological deficit (especially that of a functional nature) even though they may suffer from intractable pain that is every bit as distressing and debilitating as that suffered by patients who also have major neurological damage: such as post-stroke patients, those with severe multiple sclerosis or complete spinal cord injury.

This technique is designed to strengthen the ligaments around the spine. Ligaments which hold the vertebrae in alignment may weaken or may be injured for instance during heavy lifting. Some doctors contend that back pain is not related to disc degeneration (which is a normal ageing process) but is due to instability of the vertebrae secondary to weak ligaments: this leads to inflammation and pain. Authors such as Dr. Ron Kennedy() suggest that prolotherapy is the way forward in treating this problem, in preference to spinal surgery involving fusion of the unstable vertebrae.

Whilst it may be true that after fusion, instability in the spinal segments above or below the fused area may develop, nevertheless, the rationale behind prolotherapy needs further investigation before we embrace this rather empirical treatment.

For the time being, this is not recommended as there is a dearth of information regarding results or adverse effects of its use.

Earlier this year, at the American Academy of Neurologists, doctors presented a report about the use of botulinum toxin (from the botulism bacterium clostridium) injected in small amounts into the muscles along the spine: this relaxes them and relieves back pain for up to 4 months. Botulinum toxin is a potent neurotoxin that blocks cholinergic nerve receptors.

In a study of 28 patients with chronic back pain, five injections were given (some patients were given saline for comparison). 6 of the patients had had previous back surgery. 11 of 14 patients receiving Botox injections experienced significant relief.

Botox injections have been used previously to relieve spasticity() or torticollis( a painful condition where the muscles of the neck spasm to such as degree that the head is held bent over to one side) It has also been used to treat hyperhidrosis (excessive sweating): a study was done in Germany in 1998, which found that Botox injected into the skin of the affected areas successfully reduced the problem for up to 20 weeks and re-injections completely removed the symptoms: all sweating was stopped in those areas. In 1999, Reuters Health() reported on injections of Botox used for migraine prophylaxis: injections were administered in a Californian study: primarily in the forehead and temple: there was successful reduction of migraine symptoms, including abortion of acute attacks within 1 and a half hours of treatment.

No serious adverse effects were seen in these studies (mostly there was only localised discomfort and bruising around the injections sites), but this preliminary work needs to be followed by larger controlled trials to assess efficacy and safety. No data is available for safety in pregnancy so it is not recommended for use in women of child-bearing age without contraception or to pregnant or nursing mothers.

Dr. S. A. Andreae-Jones MB BS

Patron of the Arachnoiditis Trust

July 2000

NOTE: THIS IS AN EXCERPT FROM THE FULL ARTICLE ON INVASIVE PROCEDURES TO TREAT CHRONIC PAIN: which is available from the Arachnoiditis Trust (contact e-mail arachnoiditis@cableinet.co.uk )

This is part of a series of articles about treatment of chronic non-malignant pain.

Others available include:

TREATING CHRONIC PAIN WITH OPIOID MEDICATION(EXCERPT: OPIOID MEDICATION)

TREATING NEUROPATHIC PAIN WITH ANTIDEPRESSANTS (EXCERPT: ANTIDEPRESSANTS)

ANTICONVULSANTS: THEIR USE TO TREAT NEUROPATHIC PAIN (EXCERPT: ANTICONVULSANTS)

BENZODIAZEPINES AS ADJUVANT MEDICATION AND OTHER SKELETAL MUSCLE RELAXANTS (EXCERPT: BENZODIAZEPINES; BACLOFEN AND OTHER SKELETAL MUSLCE RELAXANTS)

LOCAL ANAESTHETICS, KETAMINE AND OTHER NMDA RECEPTOR ANTAGONISTS (EXCERPT: LOCAL ANAESTHETICS)

MISCELLANEOUS ADJUVANT MEDICATION TO TREAT NEUROPATHIC PAIN(EXCERPTS: CLONIDINE AND OTHER ADJUVANTS; CAPSAICIN, CCK ANTAGONISTS ETC.)

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS(EXCERPT: NSAIDs)