Case-based learning: management of complex regional pain syndrome with a transdermal unlicensed medication

Background

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain condition, clinically characterised by persistent, severe and debilitating pain lasting over six months; some people with CRPS experience pain for many years​[1]​. In most cases, pain affects one limb only (e.g. arm, leg, hand or foot) but it may extend to other parts of the body​[1]​. The pain feels like a combination of burning, stabbing or stinging, and it may cause tingling and numbness. It is caused by specific stimulus, but it may be triggered spontaneously. The skin in the affected area is usually extremely sensitive; for example, a subtle touch or change in pressure applied to the affected area, or change in temperature, may trigger pain​[2]​.

There are two types of CRPS, distinguished based on the absence or presence of a lesion to a major nerve. In CRPS type 1 (CRPS-1), there are no demonstrable nerve lesions and this is the most common type of syndrome, with one US population-based study estimating a period prevalence of 20.57 per 100,000 person years​[3]​. In CRPS type 2 (CRPS-2), there is objective nerve damage, most commonly caused by severe trauma​[3–5]​. The pathophysiology of CRPS is still poorly understood and additional consideration is being given to the role of psychological factors​[2,6]​. Stress is a common trigger of flare-ups, and it has been demonstrated that there may be a link between CRPS and history of depression and/or post-traumatic stress disorder (PTSD). Evidence suggests that CRPS is more prevalent in women, with an estimated female to male ratio of 4:1, and that it can affect people of any age, including children​[3,7]​. 

People living with pain experience a significant impairment to their health-related quality of life (HRQL) and many national governments now recognise long-term pain, or chronic pain, as a public health priority​[8]​. Patients with neuropathic pain are more affected compared with other types of chronic pain​[9]​. Community and hospital pharmacists can play an important role in pain management by educating the patient about the importance of self-care, physical rehabilitation and psychological support. Additionally, pharmacists can monitor the patient’s compliance to pharmacological treatment, as well as the occurrence of any unwanted side effects​[10]​. When appropriate, pharmacists may contribute further to patient-centred care by focusing on the patient and their particular healthcare needs by suggesting alternative pharmacological treatments to the physician. The goal of the triad relationship (pharmacist-patient-physician) is to reduce pain, increase mobility and improve the patient’s overall HRQL​[10]​.

Case presentation

The patient is a female, aged 37 years, with a medical history of chronic fatigue syndrome, irregular sleep patterns, PTSD and moderate Raynaud’s phenomenon (a disorder that causes decreased blood flow to the fingers and toes). The patient was diagnosed with CRPS-1, with severe intractable pain specifically centred around the left knee. The pain was triggered by various factors, including an ambient temperature lower than 32°C, subtle air movement across her skin and any noise stimuli higher than soft sounds. This extreme sensitivity is known as allodynia and it is a common presentation in CRPS, according to the variable criteria and guidelines for the differential diagnosis of CRPS​[1,11]​. The pain resulted in the patient being bedridden for extended periods of time and the lack of mobility caused a worsening in the patient’s mental health. The use of pain-related terminology in conversation, such as the name of a support group containing the word ‘burning’, or a visual representation, resulted in a sharp increase in pain experienced and often provoked a PTSD response. The patient had been offered a range of prescription and over-the-counter medications to alleviate her pain. Oral prescription medications included gabapentin and ketamine, but these caused side effects, such as tachycardia and arrhythmia, followed by breakthrough pain. The patient was selected to participate in an NHS trial with medical cannabis, which has been cited as a possible treatment for chronic pain disorders, but treatment was discontinued after one week owing to lack of tolerance to the medical cannabis​[12]​.

Treatment with transdermal unlicensed medication

In this case presentation, the treatment of CRPS is particularly challenging. The patient attempted various oral prescription medication regimes, including gabapentin and ketamine, and a short course of medical cannabis through an NHS trial. These medication regimes were used to mitigate the pain but none were deemed successful, and the side effects were intolerable. Alternative medications were considered, and the transdermal route of administration was identified as a valid option. Topical medications are designed to deliver the active pharmaceutical ingredients (APIs) directly to the skin; transdermal, permeation-enhancing medications are also applied topically but are designed to penetrate through the skin for systemic delivery​[13]​. As opposed to oral medications, the transdermal, permeation-enhancing medications bypass the gastrointestinal tract and first-pass metabolism​[13]​. As a result, the side effects commonly experienced with oral medications indicated in CRPS may be avoided​[4]​.

Transdermal, permeation-enhancing unlicensed medications are patient-specific and customisable to include different drug types, in various dosage strengths, that are delivered simultaneously in one application. As such, transdermal medications provide a way to reduce treatment complexity and pill burden, potentially improving patient compliance to treatment​[13]​. In addition, combination drug therapy may improve clinical outcomes by means of additive or synergistic properties from APIs with different mechanisms of action​[13,14]​. In light of these potential advantages, a customised, transdermal, permeation-enhancing, unlicensed medication was prescribed by the physician: ketamine hydrochloride 10% and amitriptyline 5% in a permeation-enhancing base (see Table 1). A specials company in the UK was contacted and the pharmacist confirmed that the required formulation could be manufactured for this individual patient. Topically applied unlicensed medications may be customised to include a permeation-enhancing base and APIs in variable concentrations to meet the individual patient needs. Clinical evidence and in vitro studies have validated the use of permeation-enhancing bases in pain management​[15–22]​.

The patient applied the transdermal medication to the affected area four times per day, prior to physiotherapy sessions. It was well tolerated, allowing greater compliance to treatment regimen compared with the previous oral medications. This was the only medication used by the patient to treat her CRPS at the time. Application directly to the affected site (i.e. knee) allowed for delivery of ketamine and amitriptyline into and through the epidermal and dermal layers of the skin, leading to high drug concentrations at the target site, while maintaining low systemic drug levels and thus decreased systemic side effects. The enhanced skin permeation enables topical medications to include APIs in higher concentrations than would otherwise be prescribed orally, potentially resulting in increased efficacy without compromising the safety of the medications​[23]​.

Outcome and follow-up

The patient completed a validated, neuropathic pain-specific questionnaire before and after treatment with the unlicensed medication to measure the treatment outcomes. The Neuropathic Pain Symptom Inventory (NPSI) was used to give information comparable to that provided by quantitative evaluation of pain symptoms​[24]​. The NPSI is a self-administered, easy to use questionnaire comprising 12 questions. On a scale from 0 (none at all) to 10 (worst imaginable), patients are invited to rate their spontaneous pain (burning, squeezing and pressure), paroxysmal pain (electric shock and stabbing sensations), evoked pain (brushing, pressure and contact), as well as abnormal sensations in the painful area (pins, needles and tingling). Two additional questions evaluate the duration of spontaneous pain and the frequency of pain attacks over the previous 24-hour period (see Table 2). Scoring is based on average ratings for 5 subscores (superficial, burning spontaneous pain; deep, pressing spontaneous pain; paroxysmal pain; evoked pain; and paresthesia/dysesthesia). The sub-scores were recorded on a scale of 0 to 10. A total intensity score per 100 is calculated by collating the scores from various combinations of questions​[24]​.

Prior to starting treatment with the unlicensed medication, the patient reported a very high total pain intensity score of 96 per 100. All pain subscores were rated as worst imaginable (score 10), with the exception of deep, pressing spontaneous pain and paresthesia/dysesthesia, which were rated 9 per 10. Over the previous 24-hour period, the patient reported her spontaneous pain as ‘permanently’ present with ‘more than 20’ pain attacks, which are the worst possible ratings for these two questions. To complement these responses, the patient added that a score of 10 would be triggered by the subtle air movement across her skin and any noise stimuli higher than soft sounds.

Owing to the COVID-19 pandemic and lockdowns, it took ten months for the post-treatment questionnaire to be carried out. At this point in treatment, the patient reported a significant decrease in ratings and therefore a considerable improvement of her CRPS. All pain subscores were below 5 per 10, with a rating of 0 for paresthesia/dysesthesia and 1 for deep, pressing spontaneous pain. The superficial, burning spontaneous pain and paroxysmal pain presented the highest average ratings of all subscores, with the patient explaining that this pain was triggered by psychologic stress only. The patient previously experienced severe pain and, as a result, the thought of it would trigger the onset of pain. The total pain intensity score decreased from 96 to 11.5 per 100. Over the previous 24-hour period, the patient’s experience of spontaneous pain changed from ‘permanently’ to ‘between 1 and 3 hours’, and the number of pain attacks decreased from ‘more than 20’ to ‘between 1 and 5’ pain attacks, as displayed in Table 2. The complementary responses for pain evoked by air movement and noise stimuli also decreased from a score 10 to 2. Throughout treatment, no side effects were reported. The patient noted that, initially, the pain relief lasted only around 30 minutes post-application. With the ongoing use, the pain relief lasted between applications, apart from when evoked by specific stimuli. According to the patient, the ongoing use of the unlicensed medication appears to be effecting lasting changes to her CRPS. The pain relief experienced allowed the patient to participate in physiotherapy and, as a result, she regained full range of movement and release of contracture in the region of her right knee.

Discussion

To date, no medications have been licensed in the UK to specifically treat CRPS. Physicians may prescribe a commercial medication for unlicensed use or, alternatively, prescribe an unlicensed medication instead. Different classes of drugs are well documented and traditionally used in CRPS, including anaesthetics (e.g. ketamine), anti-inflammatory drugs (e.g. ibuprofen and prednisolone), anticonvulsants (e.g. gabapentin and pregabalin) and antidepressants (amitriptyline and nortriptyline)​[2,25,26]​. Gabapentin is one of the most prescribed oral medications for CRPS treatment. It is an anticonvulsant drug indicated in epilepsy, which has been found to be useful for treating neuropathic pain​[2]​. Although the mechanism of action is not fully understood, it is believed that gabapentin interferes with the voltage-dependent calcium ion channels and interrupts the series of actions that lead to neuropathic pain​[27]​. Oral ketamine is usually reserved for severe, intractable pain, as it is a potent anaesthetic that blocks activation of nerve cell receptors, thereby decreasing pain. If all interventions fail to alleviate symptoms, ketamine may also be given intravenously in outpatient clinics on a regular basis and titrated doses​[25]​. However, these oral and IV pharmacological treatments are not always well tolerated, owing to the frequency and severity of side effects, which can include anxiety, nausea, confusion and sleep disorders, depending on the drugs used​[28]​.

There is increased interest in topically applied drugs for the treatment of neuropathic pain owing to the potential of reduced side effects and increased patient compliance. Furthermore, topically applied drugs may also help healthcare providers effectively treat their patients, while avoiding the use of addictive oral opioid drugs​[13]​. Topical ketamine and amitriptyline are a promising combination and some studies have shown its efficacy in clinical practice​[29,30]​. A case report of a CRPS-1 patient, refractory to conventional pharmacological treatment, showed that topical treatment with ketamine 10% and amitriptyline 5%, combined with a permeation-enhancing agent, was efficacious and safe, with no reported side effects. Validated questionnaires were also used in this study to evaluate patient outcomes. Following one month of treatment, the patient reported a decrease in pain superior to 50% and a few months later the pain was virtually gone​[4]​.  

Summary 

CRPS is a debilitating, chronic neuropathic pain condition that requires a multidisciplinary approach to treatment. This article discussed a CRPS-1 patient with severe intractable pain, refractory to conventional pharmacological treatment. The patient was prescribed a transdermal unlicensed medication that included ketamine 10% and amitriptyline 5% in a permeation-enhancing base. Before treatment, the patient reported a very high total pain intensity score of 96 per 100, according to the NPSI. Following treatment, the patient had a decrease in pain, with no unwanted side effects, and a considerable improvement in her CRPS. As such, topical ketamine and amitriptyline is a promising combination in pain management when incorporated in a permeation-enhancing base. Unlicensed medications may be customised to meet the individual needs of patients and are therefore a good alternative in current therapeutics.