Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
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Harald Breivik
und
Audun Stubhaug
In this issue of the Scandinavian Journal of Pain, Ellen Jørum and co-workers describe an unusual case of CRPS type 1 [1]. It is unusual in that a viper-bite must have been the precipitating cause, and the patient was unaware of being bitten until her GP saw the typical viper-bite trace in the wound a few days later. This CRPS-case is unusual also in the fact that the patient became pregnant a few months after the viper-bite and the beginning of her CRPS-pain problems. This created a dilemma for the treating physicians: Any treatment intended to reduce the symptoms of CRPS must be carefully weighed against any risk of unwanted effects on the foetus.
1 Bites by the European adder cause none or minor reactions in almost 2/3 of cases [2] and can be unrecognized by the patient as the inciting event of CRPS-1
Adder-bites are not always painful, they caused no reaction in 11% and only minor reactions in 47% of 231 cases in Sweden [2]. Therefore a viper-bite can go unrecognized by the bitten person as was the case reported by EllenJørum and co-workers [1].
Around 10% of all patients with CRPS-1 have no obvious inciting event, or the precipitating event was minor, hardly noticed, and forgotten by the patient [3]. Ellen Jørum and coworkers therefore suggest that unrecognized viper-bite could be the cause of CRPS more often then we realize. At least this could be the case in the Nordic countries where picking berries in the woods still is a popular leisure-time activity [2]. Ellen Jørum and coworkers researched the world literature and found only three case-reports where viper-bite was reported to precipitate CRPS-1 [1].
The viper species common in the Nordic countries is Vipera berus. It has a toxin that is potent enough to cause moderately severe reactions in 29%, or very severe and potentially fatal reactions in 13% [2]. The degree of reaction depends on the amount of venom injected during the bite, but probably also by the vascularity of the bitten tissue. Treatment with antivenom is necessary in those with moderate and severe reactions [2]. The painful local reaction can also be ameliorated by antivenom [2].
It is interesting that the most frequent location of a viper-bite is the upper extremity of boys and male persons (trying to kill the adder?), whereas girls and women picking berries in the Nordic woods can be bitten in their rear end when relieving their urinary bladder! One unfortunate young man could not avoid noticing the viper-bite of his penis while relieving his urinary bladder [4].
The antihaemostatic toxin of the common European adder causes capillary leakage and oedema in the tissues exposed to the toxin. Venom can also contain myotoxic and neurotoxic substances [5]. The local symptoms and signs around the bite are similar to early CRPS with swelling, discoloration of the skin, continuous pain, allodynia and hyperalgesia [5]. These symptoms on her upper arm caused Ellen Jørum’s patient to seek medical help a few days after she had emptied a garbage-bag into an outdoor garbage container [1]. Her GP had seen a number of patients with adder-bites recently, and he recognized traces of the typical two fangs bite, about 9 mm apart above the elbow area. Without his vigilance, this case of CRPS-1 would have been recorded as a CRPS-1 without a known precipitating cause.
2 CRPS with autonomic signs and symptoms: diagnosing sympathetically maintained pain
In addition to the local swelling and pain spreading to the upper arm and shoulder region, this patient had highly abnormal sweating from the arm, sweat dripping from her fingers! Ellen Jørum’s group were able to document autonomic dysfunction with the sudomo-tor axon reflex (QSART) test, they measured resting sweat output, and they performed quantitative sensory testing (QST). Clearly, this patient has a well-documented CRPS-1 with autonomic dysfunctions [1].
Ellen Jørum’s group using single nerve fibre neurography documented direct coupling between sympathetic efferent and nociceptive nerve fibres [6]. This is extremely difficult technique and we do not know for sure how many with CRPS have such direct coupling between the sympathetic efferent and afferent nociceptor fibres. We can get some indication by causing a sudden sympathetic outflow, e.g. by a sudden sound near the patient: when this aggravates the pain, the sympathetic efferent nerves somehow must be involved [7]. A simpler method is to drop acetone on the skin in the painful area; the rapid cooling will cause sympathetic efferent nerves to release nor-adrenaline. This will precipitate pain in patients having increased adrenoceptor sensitivity or up-regulated α1-adrenoceptors [8,9]. The IV phentolamine-test (1 mg/kg over 10 min), originally described by Staffan Arner and co-workers (see [10] for references) will relieve sympathetically maintained pain via its alfa-receptor-blocking effect [3,10]. Unfortunately there are both false positive and false negative test-results, therefore experienced pain clinicians try sympathetic blockades when the clinical presentation indicate autonomic dysfunction.
3 How can we treat this pregnant patient with CRPS and autonomic dysfunctions?
For this pregnant patient the options available are restricted because we have to be certain that we do not do harm to the foetus, especially when the drug or other treatments at best help some CRPS-patients, never all, and that the effects obtained are limited. Topical administration of drugs that are only minimally absorbed into the systemic circulation are probably the only guaranteed safe treatment approach – see below.
3.1 Sympathetic ganglion blockade with a local anaesthetic drug
Sympathetic blockade with a local anaesthetic drug can relieve CRPS when there is sympathetically aggravated pain [9]. Guanethi-dine intravenous regional sympathetic blockade has a longer duration of effect and has been used extensively for the benefit of many patients with CRPS. This treatment has been criticized because RCTs with fatal flaws did not document specific effect when comparing lidocaine in saline with or without guanethidine. Lidocaine IV will have analgesic effect via its metabolite (N-ethylglycine) that enhances the inhibitory glycinergic interneurons in the spinal cord dorsal horn [11]. Lidocaine will also neutralize the effect of guanethidine on sympathetically efferent nerves (see [10]). No wonder then, that they were unable to find any additional effect of guanethidine: They had not selected patients with sympathetically maintained pain, they had given an active drug (lidocaine) to which they added a drug that was neutralized by lidocaine [10].
A study (unpublished) with enriched sample of guanethidine in lidocaine-responders: A double blind study of IV lidocaine solution with or without guanethidine under propofol anaesthesia in patients who earlier had received guanethidine in lidocaine-infusions with pain relief (Torsten Gordh personal communication).
I am afraid this may be another invalid study because of the same fatal flaws as mentioned above. Study trying to find predictors of successful sympathetic blockades was not successful - but they did not select patients with documented sympathetically maintained pain [12].
One recent study did find positive effect of thoracic sympathetic blockade, but they also administered a corticosteroid with the local anaesthetic [13].
Although a ganglion stellatum block would be technically easy in this slim patient, one cannot guarantee that rare complications (injection into the carotid or vertebral arteries, epidural or even intrathecal injections) cannot happen, and therefore sympathetic blocks were postponed in this pregnant patient [1].
3.2 Pharmacological treatments of CRPS
There are a number of drugs that can help some patients, but no medication can help every patient with CRPS and there is no medication that can cure CRPS completely [14]. They are not curative; they are palliative, relieving some of the burden of pain and other symptoms. These drugs can be useful when they enable the patient to use the CRPS-affected limb, preventing further deterioration of functions, enabling appropriate physiotherapy and enabling nature’s healing powers to repair the damage from the CRPS-process on nerves, muscles and immune system.
3.2.1 Drugs recommended for neuropathic pain
For patients with CRPS-type 2 there is a nerve damage that happened during the precipitating injury (or surgery). This does not make CRPS-2 a neuropathic pain [14], but it is reasonable to try the drugs that are recommended for neuropathic pain [15]. This patient, however, does not have any nerve damage. And all drugs listed for neuropathic pain cannot be used safely during pregnancy [16], except lidocaine patch.
3.2.2 Drugs that have some supporting evidence for helping CRPS-patients
Listed below are drugs that may or may not help patients with severe CRPS-1 or CRPS-2 and I referto [14] and [15] for the mostly weak evidence that does exist. None of these can be guaranteed to be completely safe during pregnancy [16], except lidocaine trans-dermal patch because a low amount, if any, reaches the foetus:
Glucocorticosteroid is attempted in acute CRPS to dampen the inflammatory component in the early inflammatory phase of CRPS [17]. Two weeks at 30-40 mg prednisolone daily and two weeks of tapering before discontinuation [14]. For later phases of CRPS these drugs do not have any effects.
Antiepileptics: Gabapentin or pregabalin.
Antidepressants: Amitriptyline at night (sedative and relieves anxiety). Duloxetin has some evidence for relieving neuropathic pain, so it is tried in CRPS as well.
Biphosphonates do have some evidence from a small RCT, also done early on in CRPS.
Phosphodiesterase (type 5) inhibitors: Tadalafil had effect in one RCT. Sildenafil – anecdotal case reports.
Intravenous immunoglobulin has some evidence from one small RCT.
Calcitonin has some evidence for limited effect.
Ketamine in a low, sub-anaesthetic infusion may help transiently.
Opioids often create more problems with side-effects than beneficial effect on pain
Lidocaine: IV infusion, possibly an effect via the metabolite N-ethylglycine increasing the inhibitory effect glycinergic interneurons in the spinal cord dorsal horn [11] rather than its NaV-channel-blocking effect.
Lidocaine transdermal patch relieves pain from hyperalgesic and allodynic skin areas [15,18,19]. This is partly because the patch mechanically protects the hypersensitive skin areas. A limited amount of lidocaine is absorbed to act on nociceptive nerve-endings in the dermis. Very low fractions reach the systemic circulation, so that any effects on the foetus must be negligible. Lidocaine for necessary surgery during pregnancy is considered safe for pregnant women and their foetuses by the FDA, USA and similar authorities in Australia [Wikipedia].
3.3 None-pharmacological treatments that can be adopted for pregnant patients (for references see [14])
3.3.1 Physical and ergonomic therapy
Inactivity is well known to aggravate any CRPS-condition. Physiotherapists and occupational therapists can design exercises that encourage or compel the patient to use actively the CRPS extremity. This is not easy in a longstanding CRPS with contractures from persisting at defending the extremity from contact with the surroundings; allodynia causes the patient to keep the limb in protected positions. Preventing this in early phases of a developing CRPS-condition is important.
3.2.2 Psychological approaches
CRPS is not a psychogenic condition [3]. However, psychological stress and other psychological factors such as severe anxiety and catastrophic ideas may aggravate the burden of CRPS and can delay recovery [20]. Experienced psychologists certainly can help reduce the burden of suffering and are important members of the team trying to help CRPS-patients [20]. Patients with difficult to treat CRPS suffer from suicidal thoughts, which is another important aspect of this condition for which an experienced psychologist can make a difference.
3.3.3 Graded motor imagery and mirror therapy
Many patients with longstanding CRPS develop a “neglectlike” phenomenon, losing volunteery control of the extremity. This strange symptom makes physiotherapy difficult or impossible. Moseley developed a regimen with graded motor imagery and mirror therapy for longstanding CRPS [21]. Mirror therapy appears to be quite effective in some patients [22,23].
4 Spinal cord stimulation (SCS)
SCS, where available, is offered when all other appropriate therapies have failed. But SCS is also not a very effective treatment for CRPS [14].
5 Conclusions and implications
Conclusions and implications of this interesting case report [1]: CRPS clearly can be precipitated by an adder-bite; as suggested by the authors unrecognized viper-bite can be some of the 10% of all CRPS-cases where the patients cannot remember any precipitating event. The neurotoxic factors in the viper-venom can cause severe acute pain and its neutralizing antivenom removes that pain and the local inflammatory and antihaemostatic signs and symptoms successfully [2,5].Therefore, studies of antivenom maybe one previously neglected possibility for treating early CRPS-symptoms after viper-bites. However, this young woman with CRPS after an adder-bite is still pregnant as we are writing this Editorial comment. Safety first, do no harm, is especially important in this patient because all possible drugs have none or only weak evidence for effects in CRPS. Most of them can be unsafe for foetus and mother.
The lidocaine patch, appropriate physical therapy, and supporting cognitive therapy by an experienced psychologist are safe for mother and foetus. They can prevent further deterioration of functions during the remaining part of her pregnancy
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.07.005.
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Conflict of interest: None reported.
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© 2015 Scandinavian Association for the Study of Pain
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Artikel in diesem Heft
- Editorial comment
- Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain
- Original experimental
- Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
- Editorial comment
- Genetic variability of pain – A patient focused end-point
- Observational study
- COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain
- Editorial comment
- Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
- Clinical pain research
- Complex regional pain syndrome following viper-bite
- Editorial comment
- An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers
- Original experimental
- An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants
- Editorial comment
- Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions – The need for quality control with follow-up studies of patient outcomes
- Observational study
- Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic
- Editorial comment
- Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions
- Clinical pain research
- Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
- Editorial comment
- Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
- Original experimental
- Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
- Editorial comment
- Targeting glial dysfunction to treat post-surgical neuropathic pain
- Topical review
- Glial dysfunction and persistent neuropathic postsurgical pain
- Editorial comment
- Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain
- Original experimental
- Impaired recognition memory and cognitive flexibility in the ratL5–L6 spinal nerve ligation model of neuropathic pain
- Editorial comment
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- Original experimental
- Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models
- Editorial comment
- The obesity epidemic makes life difficult for patients with herniated lumbar discs – and for back-surgeons: Increased risk of complications
- Observational study
- Obesity has an impact on outcome in lumbar disc surgery
- Editorial comment
- Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain
- Clinical pain research
- Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ)
- Editorial comment
- Pain, sleep and catastrophizing: The conceptualization matters Comment on Wilt JA et al. “A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients”
- Clinical pain research
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