Abstract: Chronic algodystrophy is difficult to treat, because the disease in this stage is usually resistant to many therapies. It particularly concerns conditions with predominant severe, intractable pain and disability of the involved extremity. In these, the severest cases, searching for effective pain control therapy is extremely important. Intravenous ketamine infusions constitute a promising therapy, which appeared recently. Ketamine possesses properties of blocking central sensitization and development of neuropathic pain through its effect on NMDA receptor, a critical factor in this process. The article presents problem of chronic, refractory algodystrophy, mechanism of ketamine action in pain control, literature review on treatment outcomes and authors’ own experience in this field. Ketamine seems to be a useful option for pain control in patients with refractory algodystrophy.

BACKGROUND

Algodystrophy (AD, reflex sympathetic dystrophy, Sudeck’s syndrome, Complex Regional Pain Syndrome) is a descriptive term encompassing a set of symptoms most often involving limbs, characterized by chronic pain, edema, local vasomotor abnormalities (change in color, temperature and sweating), trophic changes and significant impairment of limb function. The syndrome is most often due to trauma, often trivial. Rarely, the cause is non-traumatic, i.e. stroke or myocardial infarction. Symptoms involve greater part of the limb, not only the place of injury, and are disproportionately intense relative to the severity of trauma [1–3]. It is not known why algodystrophy develops following trauma in some patients and in some it does not, even though they sustained the same injury and received the same treatment.

CLINICAL FORMS OF ALGODYSTROPHY

The syndrome takes several forms, which sometimes significantly differ from each other. The most important cri¬terion for the division is duration of the disease: we distin¬guish an early (acute) and chronic (late) form. Most of all, chronic algodystrophy constitutes a greater problem than the early form because it is less difficult to treat and does not exhibit tendency for spontaneous remission. Symptoms change fundamentally and hand disability, mainly due to restriction of movement and finger contractures, is brought to the forefront. During this period rest pain is not that problematic, symptoms predominate during movement and weightbearing. Clinical picture changes significantly: hand becomes colder, skin turns pale and becomes livid on lowering. Edema becomes dense, disturbances of nail and hair growth appear. Finger mobility is significantly restricted due to periarticular changes. There is usually a deficit of finger flexion and incomplete extension. Neurological symptoms may also appear in some cases: muscle tremor, hand tremor, muscle cramps and even dystonia. Dystonia is a constant, uncontrolled spasm of finger flexors, producing flexion of a single finger, several or all fingers into a fist. It is usually accompanied by pain. Neurological symptoms also include aggravating skin hyperalgesia and allodynia [4–6]. While early management of algodystrophy is relatively easy if implemented promptly, its chronic forms are often resistant to various therapies and the outcome is un¬predictable. Fortunately, late forms of this syndrome are not as common, although they constitute a greater therapeutic challenge. Hand disability due to finger contractures, not the pain, is usually the main problem.

CHRONIC, TREATMENT-RESISTANT ALGODYSTROPHY

There is a small group of patients with chronic algodystrophy, in whom the disease runs a particularly unfavorable course, becomes a source of severe, often unbearable pain, leads to total limb disability and is resistant to the majority (often to all available) of treatments – it is a so-called chronic, treatment-resistant algodystrophy.

Among 220 patients with algodystrophy treated in my Clinic, I had 12 such cases [7,8]. These were exclusively young women aged 16–40 years, in whom the syndrome developed following small trauma or trivial disorders, e.g. contusions, sprains, superficial infec¬tions or small surgeries, but not after distal radius fractures. Disease course was rapid and it progressed to a chronic phase within 2-3 months. Apart from severe pain and rapid impairment of limb function, almost constant presence of neurological symptoms such as: hyperalgesia, allodynia, tremor or dystonia is characteristic for this particular form of the disease. For those patients the most important problem is management of severe spontaneous limb pain, while impairment of hand function is usually a secondary issue. In almost all patients the disease results in almost complete hand or foot disability.

Patients suffering from this unique form of algodystrophy usually present with some psychological disorders, most often with susceptibility for depression, although it is rather a consequence of dealing with long-lasting, severe pain and disability than a cause of the disease. The reasons for progressive course and resistance to treatment of those forms of the syndrome are not known, as it is unknown why only young women suffer from it. In such extraordinary cases it is important to search for effective analgesia. Intravenous ketamine infusions constitute one such form of therapy, which appeared in the recent years.

MECHANISMS OF KETAMINE ACTION IN TREATMENT OF NEUROPATHIC PAIN

Neurogenic pain arises spontaneously in peripheral or central nervous system without stimulation of peripheral pain receptors. It is a result of nerve damage or irritation (axonal neurogenic pain) or demyelination (demyelinating neurogenic pain) [9]. Neuropathic pain is a neurogenic pain arising in peripheral nervous system. A typical example of neuropathic pain includes disorders in a course of diabet¬ic neuropathy or neuroma developing in a mechanically damaged nerve. There is no unequivocal scientific evidence corroborating the neuropathic character of pain in algodystrophy, but this component is always present in chronic forms of the disease.

Use of ketamine for treatment of algodystrophy is based on the discovery of the role of glutaminergic N-methyl-Daspartate receptor (NMDA) in the process of “sensitization” in the central nervous system. In particular situations pain pathway neurons may remain susceptible to spontaneous excitation or excitation due to subthreshold stimuli for a long period of time, which is termed “sensitization”. This mechanism lies at the background of so-called neuropathic pain. Sensitization occurs at the level of cellular metab¬olism through activation of intracellular phosphokinase A and C, phosphorylation of specific sodium channels in neu¬rons of the pain pathway, lowering their predetermined ex¬citation threshold. Glutaminergic NMDA receptor plays the key role in this process. When activated by Mg++ it opens calcium channels of sensory and pain pathway neurons, leading to their excitation. Interaction between the site of injury and central nervous system takes place through active transport of peripherally secreted neuromediators, which are transported to the dorsal horns of respective spinal cord segment and induce changes in the system of sensory pathway neurotransmitters and modulators. It results in sustenance of the elevated, peripheral stimulation-dependent cell sensitivity to subthreshold pain stimuli. This phenomenon is probably also responsible for development of abnor¬mal interpretation of touch sensation, which is perceived as pain (hyperalgesia, allodynia). Blocking of NMDA receptor leads to inhibition of those adverse reactions and reduces sensitization in the central nervous system.

Ketamine is a substance with strong NMDA-receptor blocking properties (antagonist), easily penetrates into the brain and binds with serum proteins in almost 100%. Ketamine was and still is used for induction of general anesthesia, al¬though due to its aggravating adverse effects, its use in anes¬thesiology is currently limited. However, it made a career as a drug for neuropathic pain and treatment of algodystrophy.

RESULTS OF ALGODYSTROPHY TREATMENT WITH INTRAVENOUS KETAMINE INFUSIONS

Literature data on the use of ketamine infusions are very optimistic. Correl et al. treated 33 patients with upper and lower limb algodystrophy, early, lasting less than 6 months (n=14) as well as chronic (n=19). Ketamine was administered in doses 10–40 mg/hour for a period from 1 to 20 days. Drug dose depended on individual tolerance and presence of adverse effects, while time of therapy depended on its effectiveness. Six patients (18%) received a single ketamine infusion, as its analgetic effect was observed immediately. In 18 patients (55%) treatment lasted from 2 to 5 days and in the remain¬ing 9 individuals (27%) from 7 to 20 days. Complete recov¬ery from pain was achieved in 25 people (76%), partial in 6 patients (18), while no improvement was noted in two (6%) individuals. In 10 patients (31%) improvement lasted over 6 months and in 15 (54%) between 3 and 6 months and then symptoms returned. Twelve patients received repeated treatment using this method, in all cases acquiring very good analgesic effect, which lasted over 2 years [10]. The most com¬mon side effects included feeling similar to that after alcohol ingestion, but perceived as unpleasant. Hallucinations ap¬peared in 6 patients (18%). However, this work has signifi¬cant methodological drawbacks: a heterogeneous group of patients with large proportion of early algodystrophies, di¬versified treatment protocol and ambiguous method of as¬sessment of the results, e.g. with respect to improvement in function of the affected limbs. Despite these reservations, results presented in this publication are optimistic.

Goldberg et al. presented the results of ambulatory treat¬ment of 37 patients with chronic treatment-resistant algodystrophy with intravenous ketamine infusions. Duration of therapy was 10 days (10 infusions), drug was administered in an initial dose of 40 mg over 4 hours, which was increased by 5 mg every day up to 80 mg. before the infusion patients received 2–4 mg midazolam per os (it reduces unpleasant nightmares, which accompany ketamine administration) and clonidine for blood pressure reduction. Results were assessed at the end of treatment, demonstrating pain reduc¬tion from mean 7.5 to 5.5 in VAS scale in all patients as well as improvement in limb function. In four patients (10%) pain returned to the baseline after 2 weeks from the end of therapy, in 34 (82%) after 9–11 weeks, while three patients (8%) remained pain-free for over a year. Adverse effects were observed in only 10% of patients and were unremarkable: headache and malaise immediately after ketamine infusion. Authors conclude that ketamine treatment for chronic dys¬trophies resistant to other therapeutic methods is effective and brings hope to the suffering patients for, at least par¬tial, alleviation of symptoms [11].

Shirani et al. described a case of algodystrophy involving 3 limbs (one upper and both lower limbs) in a 41-years-old pa¬tient, which developed gradually over 6 years following a minor elbow and wrist contusion. The disorder was resistant to vari¬ous therapies and only three ketamine infusions at a dose of 50 mg over 30 minutes repeated every 7 days resulted in reduc¬tion of pain from 10 to 3 points on a VAS scale. One year after the end of treatment patient remained asymptomatic [12].

AUTHORS’ EXPERIENCES IN TREATMENT OF CHRONIC ALGODYSTROPHY WITH KETAMINE INFUSIONS

Two female patients with chronic treatment-resistant algod¬ystrophy were treated in my Clinic in cooperation with an anesthesiologist. The following scheme was used:

•             Premedication: Midazolam 7.5 mg per os, clonidine 0.75 mg per os;

•             Midazolam 2 mg iv in a 4-hour infusion;

•             Ketamine infusion: 0.7 mg/kg/hour. (max 200 mg/4 hour)

in the following scheme:

– day 1 50% of a dose;

– day 2 75% of a dose;

– day 3–7 100% of a dose;

•             Intravenous clonidine, dose dependent on blood pressure.

Patients were hospitalized in the surgical department, while ketamine and midazolam infusions took place in the recovery room of the operating theatre equipped with monitored bed, under the supervision of a nurse and an anesthesiologist.

In one patient with upper limb algodystrophy the effect of gradual pain reduction began on the 3rd day of treatment, on the 4–5th day patient stopped taking any analgetic drugs and inflammatory infiltrations on the skin of the affected hand and forearmesolved. After recovery from anesthesia she re¬ported very unpleasant sensations in a form of hallucinations and nightmares inducing depressive reactions. A total of 10 infusions were administered and the patient was discharged home pain-free. No improvement in function of the affect¬ed, previously completely disabled, limb was noted. Although the patient did not suffer from spontaneous pain, attempts at passive exercise of the affected fingers caused pain, which prevented from implementation of standard exercise thera¬py. After 2 months treatment was repeated with similar effect.

Another patient with three-limb algodystrophy resistant to all treatments received infusions of ketamine and midazolam for 10 days according to the established protocol with poor effect of minimal pain reduction (from 8–9 to 7–8 accord¬ing to VAS scale), which had no influence on reduction of consumption of analgetic drugs (i.a. methadone). In this patient ketamine did not induce such unpleasant sensations during sleep as in the first one.

Our experience with this therapy is limited and not as op¬timistic as that reported in the literature. However, this method brings hope to the most severely ill patients who cannot be offered any other reasonable treatment option. Therefore, we intend to continue with this treatment in other patients, reserving it for chronic, treatment-resistant cases. Using this method for management of early algodys¬trophy does not seem reasonable, since there are other, ef¬fective methods of treatment. Lack of functional improve¬ment after treatment is a significant drawback but, as I have already emphasized, control of pain is fundamental for pa¬tients with most severe forms of algodystrophy, while func¬tion of a limb (hand or leg) is of secondary importance.

Polish Orthopedics and Traumatology, 2014; 79: 37-40

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3.            Żyluk A: Kryteria diagnostyczne pourazowej algodystrofii. Pol Merk Lek, 1997; 2: 126–29 [in Polish]

4.            Marshall AT, Crisp AJ: Reflex sympathetic dystrophy. Rheumatology, 2000; 39: 692–95

5.            Patterson RW, Li Z, Smith BP et al: Complex regional pain syndrome of the upper extremity. J Hand Surg, 2011; 36A: 1553–62

6.            Żyluk A, Puchalski P: CRPS: observations on diagnosis, treatment and definition of a new subgroup. J Hand Surg, 2013; 38E: 599–606