Nocebo-responsive patients and topical pain control agents used for orofacial and mucosal pain
This chapter deals with two distinct topics: topical medications and the nocebo-responsive patient. They are combined here because in many ways they are related, since many patients who are reluctant to take oral medications will use topical medications. Moreover, no book that focuses on the use of medications as a part of the therapeutic process is complete without a discussion of the issues of medication fear (pharmacophobia) and anxiety-induced nocebo reactions. We briefly review the basis of the placebo- and nocebo-responsive patient and how these two psychophysiologic reactions affect treatment choices. This is followed by a detailed discussion of the topical medication options available to the orofacial pain practitioner.
5.2 Nocebo-Responsive Patients
Most people understand that a placebo reaction is when a patient feels and reports a benefit even though the patient is taking a medication that is an inert or inactive substance. The opposite of this is the expectation and experience of a negative result or side effect even when the medication being administered is an inert substance.1 This negative effect is called a nocebo response, which is considered to be a phenomenon that is exactly opposite to the placebo effect.2 This response is robust enough that it can be induced experimentally in healthy normal subjects by simply delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. The mechanism of the patient’s negative expectations of pain worsening is thought to be an anticipatory anxiety reaction and is mediated in the brain with the neurotransmitter cholecystokinin (CCK). This neurotransmitter, in turn, facilitates pain transmission; further proof that this is the correct mechanism is that CCK-antagonists have been found to block this anxiety-induced hyperalgesia.3 These findings underscore the important role of cognition and expectation in the therapeutic outcome. The two questions that arise once you understand the nocebo response are: “How do you provide informed consent about the drug you are prescribing without implanting an expectation of negative results?” and “Does this reaction occur in everyone or are some patients more susceptible than others?”
With regard to the first question, the ethical practice of medicine necessitates that we must let patients know about both the risks and benefits of a treatment so that they can elect to participate in the treatment or not. This is called informed consent and it is not optional. On the other hand, how you present this information is critical and it is well known that a positive attitude suggesting treatment success is much more likely to result in success than a neutral or negative attitude about success. For example, one method, called motivational interviewing (MI), is an attempt to systematically and positively influence the doctor–patient interaction. In the case of the pharmacophobic patient, motivational interviewing would be defined as a nonjudgmental, nonconfrontational, and nonadversarial interview with the goal of attempting to increase the patient’s awareness of their high responsivity to medications: educating the patient about the potential benefits of medication that suppresses pain activity, the concept of titration of medications to allow for adaptation, and the potential problems caused by an anxiety-induced nocebo reaction. The influence of this method on treatment outcome of patients being prescribed type-2-diabetes medications was examined in a study that looked at how training physicians in MI affected the attitude to behavior change in patients diagnosed with type 2 diabetes.4 They performed a randomized controlled trial including two groups of physicians; half were trained in MI and half were not. The two groups of physicians treated 265 type 2 diabetic patients. Patients treated by the MI-trained physicians were found at 1-year follow-up to be significantly more autonomous and motivated in their inclination to change behavior (including using their medications properly) after 1 year compared with the patients treated by the control group of non-MI-trained physicians. Finally the authors of a 2009 review of the literature on the issue of medication adherence was published suggested that MI methods were potentially helpful in altering patient behavior.5 They also recommended that prescribing doctors need to (1) devote time during the treatment visit to address medication adherence issues; (2) assess the patients’ motivation to take prescribed medications; and (3) identify and address potential barriers to treatment adherence. Of course, this review focused on psychoactive medications, but it is logical to assume its findings also apply to pain-medication adherence.
With regard to whether there are patients who are more susceptible to a nocebo response, it is fairly easy to recognize nocebo-responsive patients: they will generally tell you who they are if you simply ask them how prone they are to have all of the side effects of a medication, often at a subtherapeutic dose. This reaction is generally considered a combination of attitudes and learning. One recent study examined the role of learning on the nocebo reaction.6 In the study, healthy volunteer subjects were given verbal suggestions of pain increase before administration of either tactile or low-intensity painful electrical stimuli. The authors reported that verbal suggestions turned tactile stimuli into pain and low-intensity painful stimuli into high-intensity pain. Another study examined medication attitudes by categorizing 92 participants in an outpatient psychoeducational program as either pharmcophilic (n = 59) or pharmacophobic (n = 33) according to the Drug Attitude Inventory scale. They then examined these patients for associated factors that may have influenced these attitudes.7 The patients in the study were suffering from schizophrenia or schizoaffective psychoses. The authors reported that the two groups did not differ significantly with regard to most sociodemographic variables, clinical symptoms, or classic personality traits such as locus of control, self-concept, and quality of life. The only differences that were significant were their prior experience of desired or undesired reactions to medications and their prior hospitalization history. In 2009, another study was published which reviewed the factors influencing the occurance of adverse drug events in analgesic clinical trials.8 This study examined all adverse-event data from the placebo groups in studies on antimigraine drugs. The various active agents being studied in these trials were from the nonsteroidal anti-inflammatory drug (NSAID), triptan, and anticonvulsant drug classes. The adverse event profiles for patients in the placebo arms of the three drug classes were compared. They authors reported that the adverse events in the placebo arms corresponded to those of the antimigraine medication against which the placebo was compared. In other words, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of the anticonvulsant drug trials. The authors concluded that the negative side effects that occurred were not randomly distributed in the placebo-arm patients but were probably induced as a direct result of what these patients were told to expect as potential negative effect.
In summary, anxiety-prone, nocebo-responsive patients who have developed a pharmacophobic attitude toward some or all medications, if not handled properly, will not be able to tolerate or be willing to even try medications that could help them. As mentioned previously, these patients are usually identified as highly anxious patients who have had prior negative experiences with medications. Above and beyond their unwillingness to use medications that would potentially control their disease, these patients often fall prey to the medical predators. The definition of a medical predator is an individual who diagnoses diseases that are not recognized as ligitimate and provides treatments, often expensive, that have no reasonable evidentiary basis.9,10
For all patients, but in particular the nocebo-responsive patient, what is said to them about the medications being recommended is critical to the outcome. It is often to these patients that we recommend topical medications (covered in Sec. 5.3) since this is the only therapy that can be given without a substantial adverse reaction. It seems logical to recommend that all pain practitioners should read about and understand the principles underlying motivational interviewing because exactly what is said to a patient is probably far more important than is commonly understood by most healthcare practitioners.11
5.3 Topical Pain Medications: What Are They and Why Use Them?
In the field of pain medicine, the two most common types of topical pain relievers are those that contain local anesthetics (usually lidocaine or benzocaine) and those that contain analgesics (usually salicylates or NSAID-type medications). These two types of medications generally result in (1) a diminished propagation of nociceptive signals along the sensory neurons by blocking sodium channels and (2) local decreased production of inflammatory mediators in the tissue to which they are applied. Topical preparations of medication are usually applied to the skin as a cream, ointment, gel, aerosols, or patches but with orofacial pain conditions they can also be used intraorally as prepared as lozenges, sticky pastes, and mouthwashes (covered later in this chapter).12 Because of their rapid onset and low side-effect profile, topical medications offer a distinct advantage over systemic administration for those orofacial disorders that are regional, near the surface, and chronic and that demonstrate some response such as pain relief to topical or subcutaneous anesthetics. This chapter does not discuss transdermal patches for systemic drug delivery but instead focuses on topical local delivery of drugs, where the systemic levels of the drugs are miniscule or nondetectable. This chapter reviews the literature available on the efficacy of both custom-prepared and commercially prepared topical preparations. The specific use of topical and locally injected corticosteroid agents for mucosal pain and ulceration is covered in Chapter 12, not in this chapter.
As mentionend, topical medications have several distinct advantages over orally delivered mediations. First they are more likely to be accepted as a viable form of treatment in the highly anxious nocebo-responsive patient and in the polypharmacy and elderly drug-intolerant patient. One reason for their popularity is the widely held assumption that they produce a higher concentration of the drug at the site of application and have low or even negligible systemic blood levels. If this is true, then topical medications will produce fewer or no adverse drug effects other than local skin-based side effects. In 1998, a study examined local skin concentration versus plasma levels of acetylsalicylic acid after either a topical application of an aspirin in a diethyl ether mixture or oral aspirin.13 Nineteen neuralgia patients were given either a single 500-mg oral dose of acetylsalicylic acid (ASA) or a topical dose (750 mg) of aspirin with diethyl ether (ADE) daubed onto the painful skin. Pain relief was scored before and after treatment and the data showed that topical application of ADE produced a significant decrease in pain (by 82.6%) compared with only a 15.4% decrease after oral ASA administration. Skin concentrations were highly elevated with topical application but not oral and there were no active drugs in plasma after topical administration. Of course this study cannot be generalized to all topically applied medications and especially those that are used inside the mouth, where patients are more likely to swallow a portion of the medication. With different medications, vehicles, and sites of application, there will be variable degrees of systemic absorption.14
Another potential advantage of localized applications is that due to the general lack of drug interactions a higher dose can be given initially because there is a diminished need to titrate doses to tolerability, which is often necessary in the elderly. It is quite clear that, with the elderly, topical medications are very popular. A 2006 study looked at the use of self-prescribed nonprescription medications and dietary supplements among residents of assisted living facilities.15 A descriptive cross-sectional study was performed at two assisted living facilities in Oregon and Washington state that included a convenience sample of 45 assisted living facility residents. The main outcome measure was the prevalence and types of use of self-prescribed over-the-counter (OTC) medications and dietary supplements, misuse of these products, and participants’ opinions concerning use of these products. The 29 women and 16 men with a mean age of 84.8 were using self-prescribed OTC medications and dietary supplements at the time of this study. The results showed that a mean of 3.4 products was used per participant. Nutritional supplements were most frequently used (32% of products), followed by gastrointestinal products (17%), pain relievers (16.3%), herbals (14.4%), topical products (12%), and cold or cough products (8.5%). Potential misuse of these topical medications was identified in 23 (51%) of the participants. These misuses were duplication (70%), potential drug–disease–food interactions (20.8%), and inappropriate use (9.1%). The majority (76%) of the participants believed the products were helpful in maintaining health, 56% of them wanted more product information, 49% sought product information from family and friends, while only 40% turned to their physicians and nurses for information, and 11% asked pharmacists for advice. The authors concluded that the use of nonprescription medications and dietary supplements among assisted living facility residents was high, and simultaneous use of multiple products with the same active ingredient was the most prevalent problem.
The contraindications for most topical agents include broken or inflamed skin, burns, open wounds, atopic dermatitis or eczema (skin disorders), a severe liver or kidney disease, and a history of methemoglobinemia (defective iron in the red blood cells, which inhibits oxygen delivery to tissues). Finally, topicals cannot be used on individuals who have an intolerance to any of the ingrediants or in severe asthmatic patients. Safe and effective use of a topical pain-relieving agent involves many of the same considerations as if taking an oral medication.
5.3.A Commonly Used Topical Medications for Orofacial Neuropathic Pain
The medications often used for oral and perioral neuropathies are the topical anesthetics benzocaine and lidocane and the neuropeptide capsaicin; however, other compounds such as NSAIDs (diclofenac, ibuprofen, and ketoprofen), the sympathetic agent clonidine, and the N-methyl-D-aspartate (NMDA)–blocking agent ketamine hydrochloride are also used. Because the evidence supporting the use of topically applied anticonvulsants, tricyclic antidepressants, and antispasmodics is nonexistent, these medications are not covered here.
Local anesthetics delivered topically are used widely for minor pain-inducing surgical procedures and injections,16 but they also have been used for some types of chronic pain. Basically, if a neuropathic pain can be shown to be responsive to topical anesthetic in the office, then patients are taught how to apply the anesthetic agent several times each day. The goal is to maintain local numbness, reduce ectopic neuronal firing, and thereby reduce the peripheral neural sensitization. Complete cessation of pain on application of topical anesthetic may not be possible, as some of the neuronal changes may be central or due to neuropathic changes in neural tissues not easily reached by most topical anesthetics. The European Federation of Neurological Sciences established some recent guidelines regarding the pharmacologic treatment of neuropathic pain.17 The guidelines evaluated the existing published evidence in the Cochrane Database and in Medline and concluded that high-level evidence was available on the efficacy of topical lidocaine for the treatment of postherpetic neuralgia.18–20
Formulations and Dosing of Topical Anesthetics
One commonly used over-the-counter oral product that contains a local anesthetic (benzocaine 20%) is Orobase®, which is a sticky ointment that can be easily applied to the oral mucous and gingival tissue. It is used mostly intraorally, but it can also be applied extraorally. This is usually done by applying the agent to the painful facial site and then covering it with a clear plastic adhesive sheet, which keeps the anesthetic in the desired area.21 Intraoral application usually requires a custom-made oral tissue-covering plastic stent that keeps the medications in the desired mucosal or gingival location. Topical lidocaine also comes as as a 5% transdermal patch and it is approved by the US Food and Drug Administration (FDA) for postherpetic neuralgia pain.22,23 It requires a prescription and the patch is applied to the skin over the painful area. In theory, this medication decreases the neuronal firing in this area and thus relieves the pain.24 Topical lidocaine is also available as a 5% viscous liquid for severe oral mucositis. Maximum recommended doses are 4.5 mg/kg, up to a total dose of 300 mg, to avoid lidocaine toxicity, which is characterized by central nervous system changes.25 Lidocaine (2.5%) combined with prilocaine (2.5%) also comes in a paste and is called a eutectic mixture of local anesthetic (EMLA). This combination medication rapidly numbs the skin or oral mucosa for a period of 2–3 hours. When used in the oral mucosa, this mixture is a superior topical anesthetic agent for pain reduction, although it requires an extended contact time of several minutes for the area to be anesthetized.26,27 The plasma concentrations of lidocaine and prilocaine show peak concentrations well below known toxic levels 45 minutes after skin application of 8 g of 5% occluded EMLA.28
With the exception of allergic sensitization and methemoglobinemia, an emergency medical condition characterized by cyanosis and dyspnea, systemically induced toxic reactions to topical anesthetics are very rare.29–32 The most frequently reported adverse event is mild to moderate skin redness, rash, or irritation at the patch application site. However, it should be noted that, in late 2006, the FDA’s safety information and adverse event reporting program notified healthcare professionals and consumers about the serious public health risks related to compounded topical anesthetic creams.33 The FDA issued warning letters to five firms to stop compounding and distributing standardized versions of topical anesthetic creams, marketed for general distribution. Exposure to high concentrations of local anesthetics, like those in the compounded topical anesthetic creams, can cause grave reactions, including seizures, irregular heartbeats, and death. Compounded topical anesthetic creams are often used to lessen pain in procedures such as laser hair removal, tattoos, and skin treatments. They may be dispensed by clinics and spas that provide these procedures, or by pharmacies and doctors’ offices. These creams contain high doses of local anesthetics, including lidocaine, tetracaine, benzocaine, and prilocaine. When different anesthetics are combined into one product, each anesthetic’s potential for harm is increased. This potential harm may also increase if the product is left on the body for long periods of time or applied to broad areas of the body, particularly if an area is then covered by a bandage, plastic, or other dressing.
Efficacy of Topical Anesthetics for Chronic Orofacial Pain
There is one randomized blinded study that provides data demonstrating the efficacy of lidocaine for chronic oral neuropathic pain.34 Unfortunately this study examined the immediate effect of injected lidocaine, rather than topically applied lidocaine, on 35 consecutive patients with atypical odontalgia (AO). The study compared 1.5 mL local anesthesia (20 mg/mL lidocaine and 12.5 µg/mL adrenaline) versus a similar volume of saline (9 mg/mL NaCl solution) as the control injection. These injections were performed in the painful area and a visual analog scale (VAS) pain score w/>