Breakthrough Pain Treatment Across the Continuum

Author: Daniel S. Bennett, M.D., DABPM

Description: Interview with Daniel S. Bennett, M.D., DABPM

Byline: Daniel Bennett, M.D., DABPM:
I am an interventional spine medicine and pain medicine physician, practicing in Denver, Colorado. I am the medical director of Integrative Treatment Centers in Denver, Colorado, and the founder of The National Pain Foundation (www.painconnection.org). I currently serve on the Board of Directors of the North American Neuromodulation Society (NANS) and The National Pain Foundation (NPF). My disease interests lie in neuropathic pain including the complex regional pain syndromes (CRPS also known as reflex sympathetic dystrophy [RSD] or causalgia), nerve root injuries, interstitial cystitis, and failed back surgical syndrome. In addition to an extensive sub-specialty practice involving neuromodulation (spinal cord stimulation, nerve root stimulation, sacral nerve stimulation, and spinal (intrathecal) drug delivery (drug administration systems [DAS]), I also consult regarding pharmacotherapeutics for the treatment of chronic pain and have an active role in clinical pharmacotherapeutic research.

JG:
Thank you. Our focus today is going to be on breakthrough pain, but I would like to get in to balanced analgesia and the pain treatment continuum that I have heard you speak about often. First off, can you tell me about your philosophy about the treatment of patients with pain.
DB:
I favor a straight forward approach in dealing with patients. This approach can be summed up in what I refer to as the 'ABC's' of pain medicine (Figure 1):

• Ask your patient what is 'hurting' them (i.e. why are they seeking treatment),
• Believe what the individual (person) is telling you - far too often we as physicians discount what we are being told by our patient (this is a major source of treatment error when dealing with pain complaints).
• Choose the appropriate therapy for the patient. Unlike many specialties, pain medicine requires the knowledge of multiple disciplines of medicine in order to effectively treat the individual who lives with pain. I have therefore found an 'ala carte' approach as the most effective - there usually is no one absolute treatment, but the choice agreed upon by the practitioner and the one suffering should rely on the specific needs of that individual.
• Deliver what you promise. It is no sign of weakness to inform a patient you are not able to provide what they need - to deliver a complete solution for an individual, it is vital to have a network among disciplines and use it.
• Empower the patient - the number one complaint among people living with pain is they have lost control. Facilitate the education and control of the patient in the decisions regarding their care. That is not to say that we should allow abuse, but rather enlist the person who is suffering as a member of the treatment team. I believe this is the ultimate responsibility of any teacher (i.e. physician).

While some physicians rely on laboratory data/objective physical findings and such, I believe you miss the mark in pain treatment by focusing only on these traditional (i.e. allopathic) approaches. This is not to say that we should not use these in the definition of structural pathology (one would be remiss to not do this). We cannot directly measure pain, and thus what we observe is the summation of how the particular pain signal (i.e. stimulus) affects the individual person (i.e. pain behavior). Obviously, what is presented to us is the summation of the layering of the supratentoral processes that make us individual as human beings.

Therefore, my philosophy in treating people who live with pain is to recognize their individuality, and incorporate what I understand of pathophysiology with the effects to them as a person. This allows the individual direction of care to optimize the functional outcome, which I believe is the most important determinate in successful treatment.

JG Can you discuss various manifestations of pain, including gender, socioeconomic and cultural differences?
DB As I mentioned, what presents in our individual practices is not a 'pain signal', but rather a behavioral response. (Figure 2) The best way to begin to understand this is by way of an illustration: Two women in a post anesthesia recovery unit (PACU) are being cared for by a PACU nurse. The first woman has had a cesarean section, delivering healthy twins. The second is a woman in her late 30's who is childless, having undergone a complete hysterectomy for uterine CA. The same surgeon treated both women. Both have essentially the same incision, both have involvement of common pathways. The first complains of mild-moderate pain, the other complains of severe and unrelenting pain.

Why? Although the same peripheral nerve/spine pathways are involved, one has greater pain complaints than the other. The pain behavior is different, even though the pain signaling is probably equivalent. This can be explained by the different 'filters' that occur in pain signal interpretation. In the first patient, healthy children are the culimation of pregnancy and delivery (albeit requiring surgery); in the later, inability to carry a pregnancy with finality being a surgical procedure which will forever preclude carrying a child plays a crucial role in the pain signal processing. In summation, the manifestations of pain (pain behavior) are the result of a complex interaction of an initial (or perpetuated) pain signal with the overlays of gender, cultural influences, socioeconomic status and learned responses.

JG: OK. Now for some science. I have heard you lecture on our knowledge of the detailed physiology of pain. Can you review that for us, keeping in mind our focus on breakthrough pain.
DB: In the normal state, signals arrive at the nociceptor-dorsal root ganglion (DRG) via A-delta fibers (small myelinated) and C-fibers (small unmyelinated). (Figure 3) This causes a predominate glutamate discharge. Glutamate causes Na+ influx and K+ efflux, producing a change in polarity (via AMPA mediated ion channels). K+ feeds back on the nociceptor and shuts this process off. Note that NMDA receptors sit quietly with a Mg++ plug.

With a sustained nociceptive signal (i.e. untreated acute pain or sensitized mechanoreceptors/pressure receptors due to injury), Glutamate bombardment at the nociceptor-DRG leads to dislodgement of the Mg++ plug, making the NMDA receptor primed for glutamate. This priming, leads to a shift from a primarily AMPA mediated Na/K signal to a NMDA Ca++ channel. The consequences of increased intracellular calcium leads to formation of nitric oxide synthase via protein kinase C (PKC) which in turn leads to the formation of nitric oxide (NO). NO diffuses into the nociceptor/DRG synaptic space and via guanyl synthase mediated channels, prevents K+ shift, essentially preventing turn-off of the circuit. This then leads to a 'self perpetuating' circuit. NO additionally causes release of substance P from the nociceptor terminal which via neurokinin-1 (NK1) receptors leads to the formation of c-fos (early oncogene) production. Once the nociceptor-DRG complex is 'sensitized', this predisposes a normal inciting stimulus (i.e. brushing against skin) to produce an allodynia or hyperpathic response (i.e. burning or lancinating dysesthesias). Recruitment of these 'sensitized' nociceptors can be dermatomal or nondermatomal depending on the degree of segmental and suprasegmental pathways affected.

JG: So, can you give us an example of the probable physiology of a breakthrough pain episode?
DB: Simply put, painful input (i.e. via chemoreceptor, mechanoreceptor) from the periphery causes a spinal response (via nociceptor/DRG terminals). Based on the balance of excitatory and inhibitory mechanisms, the pain message is transmitted to the brain via laterally lying fast fiber tracts (neospinothalamic tract) and medially lying slower fiber tracts (paleospinothalamic tract, spinomesencephalic tract and spinoreticular tract) for perception. Convergence of these fiber tracts in the thalamus produces antinociceptive responses (e.g. sympathetic discharge [which in normal physiologic states reduces blood flow to area of injury, in part, diminishing inflammatory mediators]) and via cortical convergence, cognitive responses. It is important to understand that in this discussion of breakthrough pain, we are only discussing peripheral-cord-brain pathways typical of nociceptive pain; neuropathic breakthrough episodes secondary to 'wind up' phenomena within the segmental and suprasegmental levels (cord) are not being considered – for the most part, this type of ‘non-persistent’ pain would probably not respond as favorably to opioids alone (although there is emerging evidence that the more lipophyllic opioids are significantly more effective, probably in part due to the weak competitive NMDA-antagonistic effects exerted by these agents).

JG: So, if a patient is having breakthrough pain (BTP) episodes, describe your initial assessment:
DB: It is important to remember that breakthrough or 'episodic' pain comprises several categories. It can be classified as:

• Incident pain - directly related to activity.
• Spontaneous or episodic pain (unrelated to a particular activity), or
• End-of-dose failure of the sustained-release medications.

The goal of assessment should be to define the type of breakthrough pain so that you can determine how best to treat it. An example of this is a patient who undergoes a two level lumbar fusion, say a posterior lateral interbody fusion (PLIF) who is in the acute post-operative phase. This patient has true incident pain related to surgical insult (i.e. incisional pain, pain with movement associated with allograft harvest site, etc.). This patient may also have spontaneous or episodic pain related to previous nerve entrapment (say L4 radiating to anterior thigh). They also may experience an end-of-dose failure secondary to significant CYP-2D6 activation from various anesthetics used along with concomitant medication therapy that includes SSRI's, benzodiazepines (frequently utilized for acute post operative muscular spasm); in this setting, medications are hypermetabolised (i.e. sustained release and normal release medications are processed in a shorter period of time by the liver enzyme system). If this hypothetical patient were my patient, I would treat incident pain with an incremental dose setting via a patient controlled analgesic device (PCA) so that a rapid onset of opioid is available that can be used by the patient pre-emptively (i.e. prior to dressing changes, physical therapy, etc.). For spontaneous or episodic pain I would increase (or add) a membrane stabilizer (antiseizure medication) ± a rapid onset opioid. For end-of-dose failure, (usually suspected by periodic 'bursts' of PCA usage which occur several hours apart and are unrelated to known incident pain) I would increase the amount of sustained release medication. Failure to recognize the diverse type of breakthrough pain can lead to undermedication (i.e. which can directly and negatively impact mobilization) or overmedication (i.e. which can lead to somnolence, aspiration, etc.).

JG: Do you use opioids, and what factors do you take into account when considering opioid use?
DB: I do utilize opioids as part of my overall paradigm of pain treatment. I long ago abandoned the naïve and opiophobic idea that opioids are dangerous; if one looks at side effects, alterations of mood, etc., many of the more commonly prescribed medications fit that bill – i.e. benzodiazepines, antoseizure medications, SSRI's etc. That is not to say that an opioid is appropriate for all pain (that is as ridiculous as saying that every patient with pain needs an NSAID, SSRI, or membrane stabilizer).

Once I determine that a particular character of pain exists which may be reduced from an opioid, and believe the patient has a cognitive/behavioral profile that would permit use of an opioid (often determined in concert with a medical psychologist), an opioid trial is planned.

The appropriate use of opioids should begin with a well orchestrated trial of the drug. Consider a patient with elevated levels of blood glucose and urine glucose, protein, and ketones. After a thorough workup for diabetes the patient would be given insulin and possibly a new dietary regimen, with close laboratory monitoring occurring periodically during treatment. Why should the use of opioids in a patient with pain be any different?

Before prescribing opioids, the clinician should record baseline assessments of the patient's perception of pain intensity (keeping in mind there are no standardized methods of measurement of pain perception, simple scales that have been used standardly in practice), any extrinsic psychological (co-existing) variables like depression or anxiety as well as underlying cognitive/behavioral types which may preclude treatment with opioids (or at least require ongoing co-management with a subspecialty which treats these aberrant types (i.e. medical psychologist, psychiatry)), and ability to carry out required activities of daily living (also looking at desired (and realistic) activities which enrich the individual's life). It is also vitally important to outline to the patient the purpose of the addition (trial) of opioids – to improve function with reduction of pain intensity (no cures, no promise of 'no pain'). Certainly, we all have experienced patients where palliation of the pain intensity is all that can be reasonably accomplished (i.e. functional status of the individual with regard to 'activities' is precluded by overwhelming impairment [i.e. paraplegia, quadriplegia, etc.).

As opioids are utilized, the pain/function diary will show the effects of the opioid over time. The expected results are diminished pain intensity, increased functioning, and minimal adverse events (Note: If I have a patient who presents with a 7/10 numeric intensity and 80% reduction of pre-pain function and now has 6/10 but is back to 90% of function, I consider this a therapeutic success and would probably ask psychology to work with that patient on the disparity of perception to function).

At follow up visits the clinician and patient should discuss these results to assess the efficacy of the current opioid regimen; remember, a trial may fail simply because an opioid is insufficient or not tolerated just as any other medication class can fail. The clinician should document all encounters during the trial, including opinions gleaned from review of the patient's pain/function journal — this review also serves as a data source regarding the presence of the types of pain occurring (i.e. persistent background pain [the only indication for sustained release preparations] versus breakthrough pain) so that therapy can be tailored to the individual need.

Last, there is emerging science on various (µ) mu-receptor subtypes which differ according to genetics of the particular patient. Based on this, trialing of at least two (I often trial three) differing classes of opioids is recommended prior to failure of opioid trial.

JG: So, how do you know when to choose an opioid, and how do you decide which one?
DB: Although the World Health Organization has presented physicians worldwide with a 3-step ladder guideline for choosing medications appropriate for the various levels of pain, this has serious shortcomings. Foremost is the diverse presentation of pain syndromes (i.e. a neuropathic pain syndrome obtains little benefit from a NSAID, but the risk of the medication is significant (i.e. renal damage, mucosal damage) and therefore even though pain intensity perception may be rated as low (i.e. 3/10), following a receipe such as WHO ladder is woefully inadequate). It therefore makes more sense in understanding the type of pain which requires treatment and then tailoring therapies (invasive or noninvasive) which have a reasonable chance of reducing intensity of pain and/or modifying the character of pain. If a provider does not have this knowledge base, the patient should be referred to a specialist who does.

Pain specialists are increasingly promoting the use of opioids for many types of pain. Opioids provide broad-spectrum analgesic efficacy (they reduce pain signal discharges at the periphery, nociceptor/DRG, brainstem, and possibly cortical pathways) with a favorable safety profile (actually in contrast to other medications (e.g. NSAIDS, tricyclic antidepressants) these medications have no known end organ damaging effects). While abuse of opioids has been a concern (in large part unjustifiably), there is no evidence of opioid abuse when used in appropriately selected patients, in prospective studies.

Opioids are classified broadly as hydrophilic or lipophilic, and potency is directly proportional to the lipophilicity of the drug (Figure 4). Highly lipid-soluble drugs diffuse to neural targets far more rapidly than hydrophilic drugs. Hydrophilic opioids include codeine (a prodrug [a nonpharmacology active progenor for an active drug]), morphine, hydromorphone, oxycodone, hydrocodone (prodrug), propoxyphene, meperidine, and methadone. Codeine requires enzyme activation (CYP 2D6) to produce morphine, the active opiate; in the same way hydrocodone produces 6a and 6ß derivatives which are active The prototype of the lipophilic class of opioids is fentanyl, which is highly bound. The binding activity of morphine is 60%, while fentanyl is 82%-85% bound. As potency is a property of receptor binding, the dosage would be less with fentanyl than with morphine. This can reduce the incidence of adverse events. Thus, I often chose fentanyl as a first line opioid.

The ideal opioid would be easy to take, with no active metabolic byproducts. It would be absorbed easily without inducing its own metabolism. It would work rapid to facilitate steady-state, and would have minimal adverse events. Unfortunately, no opioid now available can be considered 'ideal.' Each drug has its benefits and drawbacks. Thus it is during the formal opioid trial that one can determine if an opioid is effective, and if so which class is best for the particular patient.

JG: Do you utilize non-opioids or interventional therapies for BTP?
DB: Well, I am trained as an interventional spine/pain physician and that is a large portion of my practice, so yes. Whether or not a non-opioid or interventional (invasive) technique is utilized depends on the nature (i.e. probability of origin, whether neuropathic or nociceptive) of the pain, as well as the particular patient I am treating.

In paroxysmal neuropathic pain, which is typically sudden, lancinating pain, interventional techniques may be appropriate if one agrees with the theory of quieting pain generators (often referred to as stabilization); these would include selective nerve rootlet blockade with addition of steroid). The use of a baseline membrane stabilizing medication (e.g. antiseizure medication) can be useful in reducing the incidence and the intensity of these paroxysms of pain as well as use of a lipophyllic opioid.

Traditionally, chronic pain treatment has been based on a continuum in which pain relief progresses from the least invasive procedures to the most invasive. I am quite aware of the foundations of this, however I believe we now have enough knowledge accumulating that the invasiveness or noninvasiveness is not the issue; rather the importance of aggressive treatment to retard or prevent the development of circuits which produce intractable pain is paramount. I have therefore proposed a pain medicine paradigm (Figure 5) which stresses overall care (i.e. mind and body) with early aggressive diagnosis with treatments planned accordingly while pain is being treated. Certainly, pain may be the final disease state, but this must be proven not merely implied.

An example of this is a patient who was referred to me with a diagnosis of fibromyalgia. In review of records, it was noted that two motor vehicle accidents had occurred (prior to these no evidence of pain or muscular tenderness was reported). Examination was frought with difficulty secondary to overwhelming myofascial complaints with physical examination showing intense hypertonicity of muscles with defined trigger points coupled with extrinsic depression and anxiety secondary to over four years of pain following injury. A two week course of diazepam was followed by re-examination which reflected two major spine segments (C7/T1 and L5/S1) which produced radiating pain characteristic for facet arthropathy syndrome. Interventional diagnostics (intraarticular facet joint injection) confirmed a major generator at C7/T1 and L5/S1 [incidentially on one side]. Patient was taken for radiofrequency neurolysis (RF) of affected segments followed by a coordinated CORE stabilization by physical/manual therapy. The patient is now free of ‘fibromyalgia’ signs, only complains of occasional diminished ROM (primarily in neck) as well as seasonal flares (i.e. stiffness during acute barometric changes). Had initial evaluation been conducted appropriately, this patient would never have approached the degree of dysfunction and pain.

JG: What do you mean by “balanced” analgesia?
DB: The best example I can give is what happens during a general anesthetic in most centers. In this setting a drug coma is induced (i.e. general anesthesia) with the goals being amnesia, analgesia (pain control), hemostasis and homeostasis (i.e. all of your bodily systems controlled and minimally stressed. To accomplish this goal, an anesthesiologist may use (5) five to (10) ten different medications, many with specific actions via a receptor.

In the treatment of pain, multiple goals (i.e. pain control, maximizing function, decreasing anxiety and depression) are the norm. Giving an analgesic (usually an opioid) along with a co-analgesic usually leads to decreased drug load (therefore, diminished side-effects). Drugs acting on more than one receptor type produces a phenomena we call synergy, or 'more bang for the buck.' In these circumstances the positive effect (i.e. pain control with functional gain) may be far more than with a single medication (monotherapy) alone.
Overall the goals of balanced analgesia are reduction of:

• Peripheral sensitization
• Segmental and supresegmental (spinal cord) sensitization
• Likeliness of central sensitization

Pharmacotherapeutic targets are distributed throughout the body, from the peripheral sensory areas to the core of the central nervous system (CNS). (Figure 6). At peripheral sites, nonselective and COX-2 selective NSAIDs are used to diminish the inflammatory process, thereby decreasing overall glutamate bombardment of the nociceptor terminal. Opioids act on µ receptors in the periphery, joints, and enteric system. Adding a membrane stabilizing agent (e.g. antiseizure medication, local anesthetic) which acts on sodium channels also helps to reduce peripheral sensation.

At the spinal cord level (neuroaxium) multiple receptor sites are present. Drugs known to work at this level include calcium channel blockers (e.g., gabapentin, oxycarbazepine), alpha2 agonists (e.g., clonidine, tizanidine), GABA-nergic agonists (e.g., tiagabine)and NMDA antagonists (e.g., ketamine, topiramate, dextromethorophan) as well as opioids.

At the spinal cord axis and in the central brain, the agents include the tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs). The opioids are also effective on the axis, at both µ and d receptors.

Finally, there are medications that affect the descending pathways; serotonin and norepinephrine show considerable promise, at least in animal studies. The opioids also affect the descending pathways.

JG: Do you use any of the new delivery systems for opioids such as transmucosal or transdermal?
DB: The goal of breakthrough pain medication is to treat breakthrough pain rapidly and effectively, without over-medication (Figure 7). The pharmacodynamic qualities of a breakthrough pain agent should match the unique characteristics of breakthrough pain. The ideal breakthrough pain medication would be absorbed rapidly, provide meaningful pain relief within minutes, and be effective for moderate-to-severe pain.

In some patients, IV opioids can provide rapid onset of relief, but this route requires technical equipment, trained personnel, and invasive techniques. Newer routes of administration, including the oral transmucosal route, offer fast absorption by more convenient means. Patients who can achieve rapid pain relief often feel that they have achieved more control over their pain (i.e. empowerment) and subsequently become less anxious about potential exacerbations of pain. When patients can focus less on preventing pain, they often become more active and focused in other areas of their lives. The result is an improved quality of life.

JG: Why is the transmucosal delivery system so effective?
DB: The oral transmucosal route of delivering drugs is desirable for several reasons:

• The oral cavity has a relatively uniform (warm) temperature and a large surface area.
• The oral mucosa is highly vascularized
• The oral mucosa is highly permeable (approximately 20x more permeable than the skin

Because of these characteristics, certain drugs can cross the oral mucosa and enter the bloodstream rapidly and directly, without hepatic and intestinal first-pass metabolism. The the availability of the drug to the receptors where it is needed is increased, and rapid onset of action is achieved without invasive methods.

JG: Is fentany a reasonable alternative to oxycodone and hydrocodone prepatrations?
DB: Fentanyl is the prototypical lipophilic opioid and is the only lipophyllic opioid currently available in parenteral (IV) and non-parenteral forms. With oral transmucosal fentanyl (OTFC), there is no depot effect (in contrast, with transdermal fentanyl absorption continues for hours after the patch is removed from the skin.) Patients report a rapid onset, with initial clinical effects within (5) five minutes (a typical lozenge requires 15 minutes to complete). The peak blood level with OTFC occurs approximately 20 minutes after the OTFC lozenge dissolves completely. This is distinctly different from hydrophyllic opioids where the average clinical onset is 25-30 minutes; peak serum levels occur at approximately 45-50 minutes.

In usual clinical practice fentanyl appears to have no active metabolites. Fentanyl does not induce liver enzymes and the metabolism occurs via P450 (CYP) 3A4 subenzyme system, so coadministration with common medications (i.e. hydrophyllic opioids, SSRI, TCA’s, etc.) would have little effect on fentanyl metabolism. Because it is available in various forms, fentanyl is dosed easily and compliance is improved. There is far less constipation than with hydrophilic opioids because of reduced passage of fentanyl into the GI tract.

JG: What do you think about the abuse potential of these agents?
DB: Well, it is quite interesting that you ask that. The drugs with the greatest abuse potential are probably the ones that reach high and rapid peak plasma concentrations. Whereas it is easy for the abuser to take a handful of oxycodone or hydrocodone tablets, it is more difficult to abuse medications that are delivered transmucosally. OTFC requires a certain amount of saliva to dissolve the matrix, and therefore there is a limit to the number of units that patients can put in their mouth. This is clearly a rate limiting step for the potential abuser. As the most effective means of absorption is via the mucosa crush, chew, swallow, melt or drinking OTFC preparation would significantly limit its effectiveness, making the drug subject to significant first pass hepatic metabolism and decreased bioavailablilty.

JG: What's on the horizon for novel analgesics or therapies?
DB: Vanilloid receptor ligands represent one promising area. The vanilloids (eg capsaicin and resiniferatoxin) produce pain initially but cause a rapid secondary down-regulation of pain pathways. Since the identification of the vanilloid receptor, VR1, considerable effort has been placed on developing either less pungent agonists or antagonists for this receptor. A second emerging field focuses on neural ion channels. In this respect research emerging from Yale University School of Medicine is particularly interesting. The Na(v)1.9 Na(+) channel (also known as NaN) is preferentially expressed in nociceptive neurons of the dorsal root ganglia (DRG) and trigeminal ganglia. Na(v)1.9 produces a persistent, tetrodotoxin-resistant current and appears to modulate resting potential and to amplify small depolarizations. These unique properties indicate that Na(v)1.9 has significant effects on the electroresponsive properties of primary nociceptive neurons.

Peripheral axotomy, which is a model of neuropathic pain, downregulates Na(v)1.9 which has been proposed to contribute to the hyperexcitability of DRG neurons after nerve injury. Thus, Na(v)1.9 appears to represent a selective and effective target for novel analgesics. Third, conopeptides such as SNX-111 (now before the FDA as Ziconitide) which binds to the N-Type voltage sensitive calcium channels N-VSCS (which have good representation in the dorsal horn of the spinal cord), shows considerable promise, particularly as an adjuvant to opioids in the intrathecal (spinal) space. This medication is already in use in Europe. Of course we also could discuss ionophoresis application of current opioids or new indications for neuromodulation (peripheral nerve rootlet stimulation, spinal cord stimulation, intrathecal drug deliver via drug administration systems) but this would take up too much time. Suffice it to say, there are plenty of new indication for current technology emerging as well as novel therapies in the treatment of pain.