Etanercept (Enbrel) for Radiculitis (Sciatica)

The common and disabiling pain condition is chronic lumbar radiculopathy (chronic back pain/Sciatica). Despite the widespread promotion of treatments of neuropathic pain a recent analysis of neuropathic pain treatments has concluded the following:

“To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP(neuropathic pain).” This was certainly a surprise to me.
Pain 132 (Dec. 2007) 237–251
Review and recommendations Pharmacologic management of neuropathic pain: Evidence-based recommendations Robert H. Dworkin et al

abstract here
This suggests a great need for potential agents. Local injections of Enbrel appears to be one of them with in some cases dramatic responses despite long term misery. This is one of the agents I fear our drug plan will never carry.

Conventional Treatments DO NOT work for leg pain radiculopathy.
After all this hype that Tricyclic Antidepressants should be tried first for Neuropathic pain, it was amazing that it worked so poorly for lumbar radiculopathy, the commonest of all neuropathic pains.

Initially, although a very small study, (6 patients on Nortriptyline) there was a suggestion of modest improvement of Nortriptyline,
Pain 76 (1998) 287–296
A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain
J. Hampton Atkinson et al
However, in 2007,a larger trial found Nortriptyline faired poorly with an average dose was 84 mg.; Morphine, tested separately, did poorly as well with an average does of 62 mg.
Pain 130 (2007) 66–75
Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain
Suzan Khoromi et al.

“In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was, 14% for nortriptyline (95% CI = [-2%, 30%]), 7% for morphine (95% CI = [-8%, 22%]), and 7% for the combination treatment (95% CI = [-4%, 18%]). Mean doses were: nortriptyline alone, 84 ± 24.44 (SD) mg/day; morphine alone, 62 ± 29 mg/day; and combination, morphine, 49 ± 27 mg/day plus nortriptyline, 55 mg ± 33.18 mg/day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.”

The poor showing of morphine was not seen with fentanyl patch, where a 32% pain reduction was found in an “open label” study.
P.L. Dellemijn, H. van Duijn and J.A. Vanneste, Prolonged treatment with transdermal fentanyl in neuropathic pain, J Pain Symptom Manage 16 (1998), pp. 220–229.

Topiramate was found to work poorly for the leg pain but definitely helped the back:

Topiramate in Chronic Lumbar Radicular Pain
Suzan Khoromi,* Athos Patsalides,† Suzan Parada,‡ Vesta Salehi,*
Jennifer M. Meegan,* and Mitchell B. Max*
The Journal of Pain, Vol 6, No 12 (December), 2005: pp 829-836Abstract: Chronic lumbar radicular pain is the most common neuropathic pain syndrome. This was
a double-blind, randomized, 2-period crossover trial of topiramate (50 to 400 mg) and diphenhydramine
(6.25 to 50 mg) as active placebo to assess the efficacy of topiramate. Each period consisted of
a 4-week escalation, a 2-week maintenance at the highest tolerated dose, and a 2-week taper. Main
outcome was the mean daily leg pain score on a 0 to 10 scale during the maintenance period. Global
pain relief was assessed on a 6-level category scale. In the 29 of 42 patients who completed the study, topiramate reduced leg pain by a mean of 19% (P = .065). Global pain relief scores were significantlybetter on topiramate (P < .005). Mean doses were topiramate 200 mg and diphenhydramine 40 mg. We concluded that topiramate treatment might reduce chronic sciatica in some patients but causes frequent side effects and dropouts.

However side effects in study were bad:

“We would not recommend topiramate unless studies of alternative regimens showed a better therapeutic ratio.”

Pregabalin apparently failed in radiculopathy as well:
A.E.S.U. Remmers, L. LaMoreaux, J.P. Young, J. Moore and M. Poole,
Pregabalin treatment of patients with chronic low back pain (2000) Presented at the American Pain Society Annual Meeting, Atlanta, Georgia, November 2-5.

Given that Gabapentin is structurally very similar to Pregabalin, it is unlikely it would fare any better.

Another more recent larger study of pregabalin failed to find benefit in radiculopathy:

see:
Sciatica Pain Is Different and Does NOT Respond Much to Pregabalin (Lyrica)

WHAT HOPE IS THERE FOR RADICULOPATHY?
A Enbrel pilot study in acute sciatica was spectacular:

Ann Rheum Dis. 2004 Sep;63(9):1120-3. Epub 2004 Apr 28. Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study. Genevay S, Stingelin S, Gabay C.

They used: “three subcutaneous injections of etanercept (25 mg every 3 days)”

“Results: In the etanercept group all variables improved: VASB from 36 to 7; VASL from 74 to 12; RMDQ from 17.8 to 5.8, and ODI from 75.4 to 17.3; all p<0.001. Pain (VASL and VASB: p<0.001) and ODI (p<0.05) were significantly better in the etanercept group than in the methylprednisolone group.”

(from article above)
OK this is a busy slide;

The control group was given Methylprednisolone steroids.

VASL was the leg pains of sciatica

re VASL – The control group improved very little while the Etanercept improved 80-100%.
ODI was the Oswestry disability index, a commonly used disability score. It was significantly better in the Etanercept group and was the Roland Morris Disease Questionnaire(RMDQ), another disability measure.
Full article here

Another Pilot study, this time with hopeless chronic sciatica was :

Swiss Med Wkly. 2003 Mar 22;133(11-12):170-7. Perispinal TNF-alpha inhibition for discogenic pain Tobinick EL, Britschgi-Davoodifar S.full article here

Some of the results took my breath away. Here’s one:

“Case 4. Chronic discogenic pain; failed back surgery syndrome
This 57-year-old woman (patient 12, table 1) with a longstanding history of scoliosis treated by Harrington rod placement twenty years previously, presented for treatment of back pain and sciatica. For six years she had been experiencing constant and severe low back pain and sciatica unrelieved by three lumbar fusion surgeries. CT myelogram had revealed an extruded disk at the right L5–S1 foramen. Pain was present 24 hours per day, and both pain and numbness were experienced in the right lower back, right buttock, right thigh, right lower leg, and right foot. The patient also complained of weakness in the right leg and, to a
lesser extent, in the left leg. She was unable to walk for more than ten minutes, stand for more than ten
minutes or sit for more than fifteen minutes. Physical examination revealed intact deep tendon reflexes
in both knees, but absent achilles deep tendon reflexes bilaterally and decreased sensation in the right lateral foot. Straight leg raising was negative. Heel walking produced pain in the right lower back. Etanercept 25 mg by perispinal subcutaneous injection was administered to the lumbar region. Dramatic diminution in pain ensued within ten minutes. The patient reported 95% pain relief at one day post treatment. The Oswestry pain score prior to treatment was 60; at one month post-treatment it was 9, and at seven weeks continued to be 9. ”

This study required an average of 2.3 shots given a week apart. It was given paraspinously subcutaneously. At the time I wrote Tobinick about why it was not given as a nerve root – like block. His answer was “who are you?” as though my introduction in the letter was not enough. I did not send my CV as I didn’t think it was necessary and heard no more from him. At the time I had already tried giving it close to the nerve and found it could be initially irritating to the nerve if given as a “nerve block”. This could explain why an injection directly into an irritated disc was not helpful in a recent study:

Anesthesiology. 2007 Jul;107(1):99-105.
A double-blind, placebo-controlled, dose-response pilot study evaluating intradiscal etanercept in patients with chronic discogenic low back pain or lumbosacral radiculopathy Cohen SP, Wenzell D, Hurley RW, Kurihara C, Buckenmaier CC 3rd, Griffith S, Larkin TM, Dahl E, Morlando BJ

OH – did I mention they the failing disc study above gave only ONE shot despite the wisdom it takes an average of 2.3 shots. Initially, I tried giving just one shot enbrel to save costs; it did not work well. So an irritating shot directly in a disc only given once does not work – no surprise there.

addendum – a recent A pilot study on neck pain found good benefit:

Clin Ther. 2003 Apr;25(4):1211-8. Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults. Tobinick EL.

abstract here

The more definitive study in chronic neck and back pain was done in 2004:

Curr Med Res Opin. 2004 Jul;20(7):1075-85. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients.

Tobinick E, Davoodifar S. Institute Research Associates, A Medical Group, Inc, Los Angeles, CA, USA. etmd@ucla.edu

OBJECTIVE: Documentation of the clinical results obtained utilizing perispinal etanercept off-label for treatment-refractory back and neck pain in a clinical practice setting. RESEARCH DESIGN AND METHODS: The medical charts of all patients who were treated with etanercept for back or neck pain at a single private medical clinic in 2003 were reviewed retrospectively. Patients were treated if they had disc-related pain which was chronic, treatment-refractory, present every day for at least 8 h, and of moderate or severe intensity. Patients with active infection, demyelinating disease, uncontrolled diabetes, lymphoma or immunosuppression were excluded from treatment with etanercept. Etanercept 25 mg was administered by subcutaneous injection directly overlying the spine. Visual Analogue Scales (VAS, 0-10 cm) for intensity of pain, sensory disturbance, and weakness prior to and 20 min, 1 day, 1 week, 2 weeks, and 1 month after treatment were completed. Inclusion criteria for analysis required baseline and treatment VAS data. MAIN

OUTCOME MEASURES: Before and after treatment VAS comparisons for intensity of pain, sensory disturbance, and weakness. RESULTS: 143 charts out of 204 met the inclusion VAS criteria. The 143 patients had a mean age of 55.8 +/- 14, duration of pain of 9.8 +/- 11 years, and an initial Oswestry Disability Index of 42.8 +/- 18, with 83% having back pain, 61% sciatica, and 33% neck pain. 30% had previous spinal surgery, and 69% had previously received epidural steroid injections (mean 3.0 +/- 3). The patients received a mean of 2.3 +/- 0.7 doses of perispinal etanercept separated by a mean interval of 13.6 +/- 16.3 days. The mean VAS intensity of pain, sensory disturbance, and weakness were significantly reduced after perispinal etanercept at 20 min, 1 day, 1 week, 2 weeks, and 1 month with a p < 0.0001 at each time interval for the first dose in this patient population.

CONCLUSIONS: Perispinal etanercept is a new treatment modality which can lead to significant clinical improvement in selected patients with chronic, treatment-refractory disc-related pain. Generalizability of the present study results is limited by the open-label, uncontrolled methodology employed. Based on this and other accumulating recent studies, etanercept may be useful for both acute and chronic disc-related pain. Further study of this new treatment modality utilizing double-blind placebo controlled methodology is indicated. NOTE: This treatment method is protected by multiple patents awarded to Edward Tobinick MD, including U. S. patents 6 015 557; 6 177 077; 6 419 944; 6 537 549 and Australian patent 758 523.
The drug was not a panacea; It dropped Pain scores for 7/10 to 4.5 – 5/10 and persisted past 1 month + (length of study). On average, there was a 2 point drop in pain withing 20 minutes of being given.

The injection was given by perispinal administration as follows: “etanercept 25 mg was delivered to the soft tissue in anatomic proximity to the spine by subcutaneous administration utilizing a 23 gauge 1.5 cm needle directly overlying the midline of the back or neck, in accordance with the main area of symptomatology reported by the patient. ”
Please note it took an average of 2.3 shots to work. Also note some were epidural steroid failures, though I but maybe they were epidural steroid facilitators. By themselves, the steroid injections failed, but may have taken out some factors of inflammation not blocked by TNF inhibition. I had one lady who had epidural steroids one time and enbrel the next to tide her over to the time she could have her next epidural.

There was an initial study that demonstrated some benefit of infliximab IV infusion in scaitica.

Spine. 2003 Apr 15;28(8):750-3; discussion 753-4. Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica. Karppinen J, Korhonen T, Malmivaara A, Paimela L, Kyllonen E, Lindgren KA, Rantanen P, Tervonen O, Niinimaki J, Seitsalo S, Hurri H.

Spine. 2003 Apr 15;28(8):750-3; discussion 753-4. Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica. Karppinen J, Korhonen T, Malmivaara A, Paimela L, Kyllönen E, Lindgren KA, Rantanen P, Tervonen O, Niinimäki J, Seitsalo S, Hurri H. Department of Physical Medicine and Rehabilitation, Oulu University Hospital, Finland. jaro.karppinen@occuphealth.fi STUDY DESIGN: An open-label study was conducted. OBJECTIVE: To evaluate the efficacy and safety of infliximab, a monoclonal chimeric antibody, against tumor necrosis factor-alpha (TNFalpha) for the treatment of severe sciatica. SUMMARY OF BACKGROUND DATA: Evidence from animal studies indicates that TNFalpha plays a role in the pathophysiology of sciatica. Anti-TNFalpha therapy has not been previously evaluated in sciatic patients. METHODS: In this study, 10 patients with disc herniation-induced severe sciatica received infliximab (Remicade 3 mg/kg) intravenously over 2 hours. The outcome was assessed at 1 hour, 1 week, 2 weeks, 1 month, and 3 months after the infusion and compared to historical control subjects consisting of 62 patients who received saline in a trial of periradicular infiltration for sciatica. Leg pain was the primary outcome, with more than a 75% decrease from the baseline score constituting a painless state. Fisher’s exact test and repeated measures analysis of variance were used for statistical analysis. RESULTS: At 1 hour after the infusion, leg pain had decreased by 50%. At 2 weeks, 60% of the patients in the infliximab group were painless, as compared with 16% of the control patients (P = 0.006). The difference was sustained at 3 months (90% vs 46%; P = 0.014). Infliximab was superior over the whole follow-up period in terms of leg pain (P = 0.003) and back-related disability (P = 0.004). At 1 month, every patient in the infliximab group had returned to work, whereas 38% of the control subjects still were on sick leave (P = 0.02). None of the patients treated with infliximab underwent surgery during the follow-up period. No immediate or delayed adverse drug reactions and no adverse effects related to medication were observed. CONCLUSIONS: Anti-TNFalpha therapy is a promising treatment option for sciatica. There is an urgent need for a randomized controlled trial to evaluate whether these promising early results can be confirmed.

Another infliximab study on treatment of schmorl’s nodes (discs herniating into vertebral body) which found it needed to give four infliximab infusions. Their pain VAS scores went from 90/100 to 7/100 and from and 85/100 to 15-20/100. The former case completely cleared whereas the latter remained at 20/100
full article here

Now enter the MORON study:
This moron study has been used to refute use of TNF inhibitors:

Although all the prior studies with enbrel showed best results with regional injection of TNF inhibitors with average of 2.3 shots (first listed pilot study), and the above article with infliximab took four = 4 shots, some moron does a one shot IV study with infliximab (remicade). Earlier studies had showed 50% reduction of sciatica in the first day with remicade (above) but obviously one shot IV had no holding power.

Their one-shot not given locally but IV given study concluded:

“CONCLUSIONS: Although the long-term results of this randomized trial do not support the use of infliximab compared with placebo for lumbar radicular pain in patients with disc herniation-induced sciatica, further study in a subgroup of patients with L4-L5 or L3-L4 herniations, especially in the presence of Modic changes, appears to be warranted.”

My conclusions were that they should not let morons conduct studies. However, where ever I go to a conference this moron study is quoted because it was “randomonized and controlled” – they don’t mention it ignored all previous experience re requiring more than one shot.

I find Enbrel so helpful that at times I have paid out of my own pocket for a patient’s shot. Without the epidural steroid enhancements potentially in Tobinick’s studies, I find it will give me at least a 2-3/10 pain reduction lasting 3 months. For me, it takes 3-7 days to start working (depending how chronic) and takes TWO shots a week apart. I use a 27 guage long needle and give it paraspinously in the muslce on the side of the sciatica rather than midline. There is no need to go too deep as dispersion seems fast (some can feel it going up and down spine though I am not sure this is not placebo effect). Side effects I have seen have included one sore throat. The pharmacists like to give out enbrel preloaded syringes in groups of three – this is not necessary and don’t let anyone tell you they have to buy three. It will cost about $400.00 for two.
Warning: you can make a patient worse. The shots work and give the patient a false sense of being “cured”, though the pain will return by three months. At that point the patient will no longer be used to the pain. This will create a profound sense of despondency. Please set up a time-table and work out further shots in 10-12 weeks from the last one otherwise everyone is caught unawares.

I have an expression that fits many of my reactions to pain studies. It goes: “DIDN’T ANYONE BOTHER TO TURN OUT THE LIGHTS?”. People with radiculitis will have a large amount of myofascial accompaniment. Then there is the problem of “ceiling effect” – my take on that is that you can treat 9/10 problems a patient has and they will not necessarily feel any better because 1/10 problems can bring the pain to their ceiling of VAS-8/10. So just a plain enbrel shot may not give the results you are looking for. It will make it much easier to take out the quadratus lumborum/psoas and multifidi components, but they will still need lots of work. The leg triggers are often in piriformis, gluteal musclses, lateral calf, and posterior tibialis. They can be injected, needled and then respond to massage once the enbrel takes effect.

Very often one will find people with “myofascial pains” in shoulder, interscapular area, down arm, in buttocks and down leg. This will be associated with back or neck findings (restricted or painful movements). Since most big protrusions are gone after a years, the persistent radiculopathies are all just disc bulges, ignored by radiologists because many normals can have them. (This is so bad the bulges are NOT EVEN REPORTED; had a patient recently who had to get his specialist to specifically write that there was actually disc bulges not reported by radiologist). The problem is, CT/MRI’s cannot tell which ones are inflamed and inducing “chemical radiculitis” (discussed in another article). Some neck radiculitis cases showed positive response to nerve root block without evidence of foraminal problems at level injected. So how does one confirm radiculitis? I have found Enbrel response very useful for such and the patient is delighted by the relief of pain.

Addendum Nov. 2008 -

Joint Bone Spine. 2008 Nov 4. [Epub ahead of print] Antiepileptic drugs to treat pain in rheumatic conditions. Recommendations based on evidence-based review of the literature and expert opinion. Vergne-Salle P, Mejjad O, Javier RM, Maheu E, Fallut M, Glowinski J, Bertin P.

Reviewed evidence of help of epilepsy drugs in Chronic lumbar sciatica

1) Serpell MG, Neuropathic Pain Study Group. Gabapentin in neuropathic
pain syndromes: a randomised, double-blind, placebo controlled trial.
Pain 2002;99:557-66. – “randomized, double-blind, placebo-controlled, 8-week study in 305 patients, among whom 21 had post-laminectomy sciatica and 27 a radiculopathy”

Pain dropped in the overall groups by 1.6/10, under the 2/10 required by some groups to be considered therapeutically significant. they do make the point however, that the decrease in pain scores do not reflect the increase in “social functioning and
role emotional subscores” improvements.

Annoyingly, the majority of cases were NOT chronic radiculopathy, rather conditions like post herpetic neuralgia and CRPS which are totally different “creatures” than radiculopathy. Any benefits could be just from these cases. They also mentioned that ” 66% of patients had tried amitriptyline and 32% had tried antiepileptics” prior suggested not great responses either because they were a preselected poor responding group or because these agents are not that useful in first place.

2)

I would be interested in other people’s experience or their comments. This is one of the articles to promote coverage of these agents by the drug plan.