Using N-of-1 trials in Clinical Orofacial Pain Management

Introduction

Many orofacial pain problems are relatively easy to diagnose and can be treated successfully, but unfortunately some are not. One poorly understood pain condition, especially when it presents in the head and neck region, is complex regional pain syndrome (CRPS). Diagnosing CRPS based on history and physical examination alone can be problematic¹. Obtaining a diagnosis based on the underlying mechanism is thought to be ideal², but that often is not possible. Since some patients with CRPS also suffer from sympathetically maintained pain (SMP), sympathetic blockade with local anesthetic has been suggested to determine how that procedure affects the patient’s experience of pain³. However, positive responses may occur due to non-specific treatment effects (e.g., placebo) – especially when it comes to pain reduction with interventions^4,5. Since the prevalence of head and neck CRPS is extremely low, with only about 14 cases reported⁶, false-positive diagnostic test results are to be expected. Also, the diagnostic sensitivity and specificity of sympathetic blocks are unknown but thought to be variable⁷, and this may change in the course of CRPS, making it difficult to draw definitive conclusions from such tests.

This paper discusses an alternative approach to this dilemma, using a research-based technique to solve a single-patient problem.

Case report

A 42-year-old Caucasian female presented with constant daily pressure and pulling sensation in her left upper jaw, specifically, deep to the left maxillary first and second molar teeth (#14 and #15 in the USA labeling system). Pain was moderate to severe in intensity, aggravated with touch to the left-sided cheek, teeth and intraoral soft tissues, and worsened with weather changes, stress and frustration. Other symptoms included a report of palatal tissue adjacent to #14 and #15 having a burning swelling sensation and a complaint of limited mouth opening. Objective findings included allodynia, increased skin temperature, and decreased mandibular range of motion. These signs and symptoms fulfilled the “Budapest” clinical diagnostic criteria for CRPS¹.

Initial onset of pain was 2 years ago, diagnosed as irreversible pulpitis of #14, and treated with non-surgical root canal treatment followed by apicoectomy, resulting in maxillary antrum perforation. The patient’s pain worsened; sinus infection was suspected and treated with antibiotics, followed by root canal treatment of #15. With no relief, the patient consulted different providers (general dentist, endodontist, ENT specialist, TMD dentist, neurologist) and obtained periapical radiographs, sinus CT scan, and brain MRI. Multiple diagnoses were proposed (chronic apical periodontitis, chronic sinusitis, TMD, atypical facial pain, trigeminal neuralgia) and various treatments were provided (extraction of #14, root canal retreatment of #15, extraction of #15, TMD self-care, physical therapy, cognitive behavioral therapy, intraoral splint therapy). In addition, medication trials were attempted with various antibiotics as well as gabapentin, baclofen, amitriptyline, nortriptyline, topiramate, carbamazepine, and lamotrigine); none produced relief. Side effects with most of those medications, such as lethargy, dizziness, memory difficulties, weight gain and acne were severe, so she was reluctant to try other treatments.

How can research methodology assist clinical decision-making?

In this situation, a single subject randomized clinical trial, otherwise known as an N-of-1 trial or crossover trial, can help to refine a diagnosis⁸. The premise of N-of-1 trials is for patients to be their own control, with the intervention randomized⁹ and a predetermined end-point identified¹⁰. Thus, an N-of-1 trial would be very likely to provide unbiased information about whether sympathetic activity is a prominent component of this patient’s pain. This has profound implications for the patient, given her multiple adverse reactions to commonly used medications¹¹.

N-of-1 trial

Before beginning the trial, ethical advice was obtained and followed. Informed consent covering the nature of care, specifically including deception and emergency procedures, was obtained. The N-of-1 trial consisted of three double-blinded stellate ganglion blocks, spaced once a week, using 8 cc of injectant. A faculty colleague performed the randomization, prepared the medications, and was present during all three sessions in case rapid unblinding was needed for clinical purposes. The drugs used were 2% lidocaine without ephedrine for the anesthetic and normal saline for the placebo.

Outcome

With the blinding in place, the following was recorded:

Procedure #1: No block signs and no pain response to injection, leading to an opinion of either normal saline or a missed block.

Procedure #2: Profound positive block signs, known as Horner’s syndrome: left nasal congestion, ptosis, facial flushing, and warmth. Pain intensity increased (6/10 to 8/10), spreading into the maxillary antrum and changing from achy to a sharp, throbbing quality. The patient was unaware that Horner’s syndrome was occurring and remained blind to medication allocation. Procedure #3: Very subtle positive block changes including left arm warmth and mild ptosis. Again pain intensity increased (5-6/10 to 7/10) and spread into the maxillary antrum.

Unblinding revealed that placebo was used for procedure #1 and lidocaine for #2 & 3. The pain increase after effective sympathetic blockade implied a diagnosis of CRPS with sympathetic independent pain (SIP) rather than SMP, thus avoiding expensive and risky stellate ganglion anesthetic or alcohol blocks as an actual treatment.

Discussion

Since CRPS with SMP in the orofacial region is rare, strong research data about diagnostic testing for this condition are unlikely to be developed. However, treatment success is often directly related to obtaining the correct diagnosis^12,13. Dentists have a notable history of advancing pain treatment in the orofacial region¹⁴ and play a pivotal role in pain classification research¹⁵. With the use of traditional research methodology, clinicians can and should apply evidence-based approaches to care for individual patients, as outlined above. To address the original clinical dilemma in this case, an N-of-1 trial was performed with diagnostic stellate ganglion blocks¹⁶ to investigate a possible SMP component of CRPS. The intent of this report is not to advocate experimentation on patients but to demonstrate how solid clinical information can be obtained to advance patient care.

In conclusion, research methodology applied to patient care has the potential benefit of answering questions about individual patients when insufficient information exists to guide clinical decision-making. Since rare conditions and unexplored clinical issues may occur in the field of orofacial pain, clinicians need to be aware that the chance of obtaining false positive diagnoses in such cases is high. N-of-1 trials can be used to assist clinical decision making for individual patients.