SAMPLE COMMENTARIES:
Polyanalgesic Consensus Conference—2012: Recommendations on Trialing for
Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel
PUBLIC COMMENTARY:
The purpose of the trial is to predict as accurately as possible the long-term effectiveness of
a device before its definitive implantation. It should therefore mimic closely the conditions
of an intrathecal infusion as provided by an implanted pump. However, no single method
described in the literature, either continuous infusion or bolus injection into the epidural or
intrathecal space meets all the criteria of an ideal trial. Currently, the trial addresses only
the pharmacodynamic part of the problem, namely whether the tested drug is effective for
the pain condition presented by the patient and the side effects are tolerable.
Pharmacokinetic questions remain unanswered such as drug distribution in the intrathecal
space during slow infusion. Yet the failures encountered in intrathecal therapies are more
frequently pharmacokinetic than pharmacodynamic failures (1,2 ).
Since no method can be considered superior in predicting the long-term failures, the trial
should remain safe, cheap, and convenient for the patient and the physician and the risks it
may cause should not exceed the uncertain benefits it provides. Indeed its efficacy has not
been demonstrated so far by randomized placebo-controlled studies and long-term failures
in the literature range up to 39%, regardless of the trialing method used (3). Many of the
publications on intrathecal trials are either anecdotal, case series or case reports and do not
involve RCT's. This present report provides an objective and complete summary of the
current literature but the quality of the studies are inconstant with important
methodological problems: studied populations are heterogeneous, suffering from different
types of pain, tested with non standardized procedures and measured with different
outcomes. Moreover, many data are missing, making the results of a systematic review
inconclusive. The realization of randomized controlled trials with standardized outcomes is
therefore mandatory to determine the usefulness of a trial. Defining a successful trial is also
required. Still, it may be difficult to predict definitely the long-term efficacy of a therapy for
a more or less rapidly progressive disease.
1. Walker RH, Danisi FO, Swope DM, Goodman RR, Germano IM, Brin MF. Intrathecal
baclofen for dystonia: benefits and complications during six years of experience. Mov
Disord. 2000 Nov;15(6):1242-7.
2. Buchser E, Durrer A, Chédel D, Mustaki JP. Efficacy of intrathecal bupivacaine: how
important is the flow rate? Pain Med. 2004 Sep;5(3):248-52.
3. Hassenbusch SJ, Stanton-Hicks M, Covington EC, Walsh JG, Guthrey DS. Long-term
intraspinal infusions of opioids in the treatment of neuropathic pain. J Pain Symptom
Manage 1995 Oct;10(7):527-43.
Christophe Perruchoud, MD
Morges, Switzerland
CITATION: Deer, T. R., Prager, J., Levy, R., Burton, A., Buchser, E., Caraway, D., Cousins, M.,
De Andrés, J., Diwan, S., Erdek, M., Grigsby, E., Huntoon, M., Jacobs, M., Kim, P., Kumar, K.,
Leong, M., Liem, L., McDowell, G., Panchal, S. J., Rauck, R., Saulino, M., Staats, P., StantonHicks, M., Stearns, L., Sitzman, B. T., Wallace, M., Willis, K. D., Witt, W., Yaksh, T. and Mekhail,
N. (2012), Polyanalgesic Consensus Conference—2012: Recommendations on Trialing for
Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel.
Neuromodulation: Technology at the Neural Interface, 15: 420–435. doi: 10.1111/j.15251403.2012.00450.x
Polyanalgesic Consensus Conference 2012: Recommendations for the Management of
Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert
Panel
PUBLIC COMMENTARY:
In the absence of robust studies for diagnosis or management of clinical entities, guidelines
may be helpful in guiding physicians in clinical decision making. Guidelines are often
developed by medical societies on topics within their domains with the intent of helping
clinicians assimilate rapidly expanding medical knowledge and making appropriate
decisions about health care. Guidelines generally follow strict sequential processes
including collection of data, preparation of systematic reviews, weighing the strength of the
evidence and grading the strength of recommendations. Assessment of adaptation and
implementation of guidelines is highly desirable[1].
When evidence is significantly limited, consensus guidelines are advantageous.
Unfortunately, expert opinion and consensus guidelines represent the lowest level of
evidence. Observational studies are intermediate, while randomized controlled trials are
believed to provide the highest level of evidence[2]. The above notwithstanding, Deer and
colleagues are most esteemed in the field and are commended for establishing consensus
and providing an algorithm for intrathecal (IT) therapies to improve patient safety and
potentially outcomes of intrathecal therapy. These guidelines have set a framework for
many, if not most, interventional pain medicine specialists.
The current consensus guidelines are the fourth iteration since the original
publication in 2000[3-6]. Given the number of intrathecal agents and potential
permutations, guideline authors have attempted-- using best available evidence as well as
their collective experiences-- to formulate “lines” of therapy. However, factors such as
limited outcome data from IT studies, the “infinite” number of IT agent
combinations/rankings as well as individual author biases will invariably result in highly
controversial “consensus” statements. Hence, far too many questions may be raised
regarding the current algorithm. For instance, why is “ziconotide + opioid” 3rd line in the
Neuropathic algorithm and not a 2nd line combination? Where would “bupivacaine +
ziconotide” fall into? Why does ziconotide disappear after line 2, in the Nociceptive
algorithm? Why not ziconotide as third line combination agent along with opioid +
bupivacaine? Though ziconotide is listed as a first line agent because of FDA approved
status, how often in practice is it used as a first line agent, given its weak analgesic efficacy
and difficult trialing and titration as detailed in the manuscript? In considering fentanyl as
line 1 agent for nociceptive pain, where are the data on efficacy? Is safety good enough?
Why not use fentanyl for neuropathic pain?...
One of the limitations of all previous intrathecal consensus statements has been the
generalization of algorithms to all patients despite individual differences. The authors in
this version of the consensus guidelines attempted to distinguish neuropathic from
nociceptive pain and accordingly established different algorithms. While this is a step
forward in attempting to identify pain characteristics as a means of elucidating optimal
intrathecal treatment choices, it suffers from major drawbacks:
1) Though the International Association for the Study of Pain (IASP) scientifically
classifies pain as nociceptive or neuropathic, mixed pain is also recognized but
has not been addressed in this algorithm
2) Classification of pain into nociceptive and neuropathic while clinically useful is
difficult to establish in many patients requiring intrathecal therapy. Indeed, for
the most common indication for IT therapy (post lumbar spine surgery
syndrome), distinction between neuropathic and nociceptive pain is often
difficult to make and most patients may suffer from a mixed pain disorder with
neuropathic and nociceptive components. It is unclear if the pain is mixed in
nature, which of the two proposed algorithms should be followed?
3) Such a classification takes into consideration only one symptom (the pain
subtype) without regard to patient characteristics—which constitute more
important determinants of success or failure of the therapy than pain subtype
4) Important details related to the physicochemical properties of the intrathecal
medications (notably lipid solubility) as well as catheter position have been
omitted from discussion in the current guidelines
Indeed, classification of pain into cancer related vs. non-cancer related may be more
worthwhile as such diagnosis may have differential implications for therapy[7]. Within noncancer related chronic pain, patient age plays an important role in opioid dose escalation
and efficacy[8]. Along these lines, stratification of pain into (dermatomally) localized vs.
disseminated pain is likely worthwhile[7]. Furthermore, considering pharmacokinetics of
intrathecal agents, especially lipid solubility, as well as highlighting the importance of
catheter tip positioning are critical to successful outcomes[7, 9-12]. Given the number of
variables involved, it is obvious that simply implanting an intrathecal drug delivery system
does not impart the same outcomes in different patients with different pathologies.
Given the above, polyanalgesic intrathecal consensus guidelines are a much needed
endeavor. However, current guidelines are too generic and do not address critical patient
characteristics that are essential for success of the therapy. Future improvements in these
guidelines should focus on tailoring specific guidelines to defined patient populations taking
into consideration not only particular patient characteristics but also pharmacokinetic
properties of the drugs used and catheter tip location.
1.
2.
3.
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour
RT, Haugh MC, Henry D et al: Grading quality of evidence and strength of
recommendations. BMJ 2004, 328(7454):1490.
Ebell MH, Siwek J, Weiss BD, Woolf SH, Susman JL, Ewigman B, Bowman M:
Simplifying the language of evidence to improve patient care: Strength of
recommendation taxonomy (SORT): a patient-centered approach to grading
evidence in medical literature. The Journal of family practice 2004, 53(2):111-120.
Bennett G, Burchiel K, Buchser E, Classen A, Deer T, Du Pen S, Ferrante FM,
Hassenbusch SJ, Lou L, Maeyaert J et al: Clinical guidelines for intraspinal infusion:
4.
5.
6.
7.
8.
9.
10.
11.
12.
report of an expert panel. PolyAnalgesic Consensus Conference 2000. Journal of pain
and symptom management 2000, 20(2):S37-43.
Deer T, Krames ES, Hassenbusch SJ, Burton A, Caraway D, Dupen S, Eisenach J, Erdek
M, Grigsby E, Kim P et al: Polyanalgesic consensus conference 2007:
recommendations for the management of pain by intrathecal (intraspinal) drug
delivery: report of an interdisciplinary expert panel. Neuromodulation : journal of
the International Neuromodulation Society 2007, 10(4):300-328.
Deer TR, Prager J, Levy R, Burton A, Buchser E, Caraway D, Cousins M, De Andres J,
Diwan S, Erdek M et al: Polyanalgesic Consensus Conference-2012:
Recommendations on Trialing for Intrathecal (Intraspinal) Drug Delivery: Report of
an Interdisciplinary Expert Panel. Neuromodulation : journal of the International
Neuromodulation Society 2012.
Hassenbusch SJ, Portenoy RK, Cousins M, Buchser E, Deer TR, Du Pen SL, Eisenach J,
Follett KA, Hildebrand KR, Krames ES et al: Polyanalgesic Consensus Conference
2003: an update on the management of pain by intraspinal drug delivery-- report of
an expert panel. Journal of pain and symptom management 2004, 27(6):540-563.
Hayek SM, Deer TR, Pope JE, Panchal SJ, Patel VB: Intrathecal therapy for cancer and
non-cancer pain. Pain physician 2011, 14(3):219-248.
Hayek SM, Veizi IE, Narouze SN, Mekhail N: Age-dependent intrathecal opioid
escalation in chronic noncancer pain patients. Pain Med 2011, 12(8):1179-1189.
Bernards CM: Recent insights into the pharmacokinetics of spinal opioids and the
relevance to opioid selection. Current opinion in anaesthesiology 2004, 17(5):441447.
Flack SH, Anderson CM, Bernards C: Morphine distribution in the spinal cord after
chronic infusion in pigs. Anesthesia and analgesia 2011, 112(2):460-464.
Flack SH, Bernards CM: Cerebrospinal fluid and spinal cord distribution of
hyperbaric bupivacaine and baclofen during slow intrathecal infusion in pigs.
Anesthesiology 2010, 112(1):165-173.
Veizi IE, Hayek SM, Narouze S, Pope JE, Mekhail N: Combination of intrathecal
opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer
pain patients. Pain Med 2011, 12(10):1481-1489.
Salim Hayek, MD, PhD
Cleveland, OH, USA
CITATION: Deer, T. R., Prager, J., Levy, R., Rathmell, J., Buchser, E., Burton, A., Caraway, D.,
Cousins, M., De Andrés, J., Diwan, S., Erdek, M., Grigsby, E., Huntoon, M., Jacobs, M. S., Kim, P.,
Kumar, K., Leong, M., Liem, L., McDowell II, G. C., Panchal, S., Rauck, R., Saulino, M., Sitzman,
B. T., Staats, P., Stanton-Hicks, M., Stearns, L., Wallace, M., Willis, K. D., Witt, W., Yaksh, T. and
Mekhail, N. (2012), Polyanalgesic Consensus Conference 2012: Recommendations for the
Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an
Interdisciplinary Expert Panel. Neuromodulation: Technology at the Neural Interface,
15: 436–466. doi: 10.1111/j.1525-1403.2012.00476.x
Noninvasive Brain Stimulation to Modulate Neuroplasticity in Traumatic Brain Injury
PUBLIC COMMENTARY:
Non-invasive brain stimulation (NBS) has both diagnostic and therapeutic potential in
traumatic brain injury (TBI). A large body of NBS literature exists spanning several decades
in humans and animal models, both in health and disease, yet TBI has been seldom studied.
The few existing studies have demonstrated that NBS is useful to understand TBI
pathophysiology, and have raised the possibility for NBS as a treatment adjunct. The review
paper titled ‘Noninvasive brain stimulation to modulate neuroplasticity in traumatic brain
injury’ by Villamar et al, provides a timely and important discussion on a potentially useful
application of NBS, based on a synthesis of available data. In addition, the paper proposes
theoretical benefits and risks according to known pathophysiology.
A variety of single and paired-pulse transcranial magnetic stimulation (TMS)
techniques have been developed to painlessly and safely probe intracortical, corticocortical
(intrahemispheric as well as interhemispheric) and corticospinal networks in humans. TMS
has been used to assay local and network excitability of the brain following stroke,
representing the sum of complex and interacting pathologic processes, as well as adaptive
physiological processes. The net change in excitability identified by TMS relates well to
dysfunction and thus sets the stage for excitability modulating protocols to improve
function. These therapeutic protocols include TMS delivered repetitively (rTMS, repeated
pulses causing synaptic activity in cortex) and transcranial direct current stimulation (tDCS,
a low-level continuous unidirectional current reaching the cortex). Here, cortical excitability
is modified - outlasting the stimulation period for several tens of minutes, and thus has the
potential to positively influence altered brain excitability. When acting to restore cortical
excitability associated with neurologic dysfunction, NBS has been shown to have clinical
benefit in several classes of neurologic conditions (both acute damage and degenerative
disease), suggesting a potential benefit for TBI. However, further controlled studies are
needed with clearly defined and hypothesis-driven interventions, in well-characterized
patients. Studies in animal models will be particularly appealing to systematically explore
the most appropriate stimulation protocols with different lesion types and temporal
recovery profile.
The authors suggest that therapeutic approaches might fall within two categories;
(1) those aimed at limiting the extent of the initial injury in order to minimize further
neurological deficits; and (2) strategies that promote reorganization of neural networks.
Each of these could be useful in maximizing function following acute traumatic injury.
Single or paired-pulse investigative TMS is generally not considered a major risk in
the days to weeks post brain lesion. This may not be true for protocols with therapeutic
intent (designed to have a lasting effect), which may pose a safety risk depending on the
injury physiology and stimulation characteristics. For example, promoting increased
excitability may seem most appropriate during the sub-acute period, however in some
circumstances the use of inhibitory NBS interventions may be desirable, such as for
counteracting the excessive glutamatergic activity thought to underlie development of
seizures. They suggest that even inhibitory rTMS protocols might increase activation of
neural elements, having a deleterious effect. In this case tDCS might be warranted as a more
benign alternative, albeit differently acting. Other safety issues discussed include the effects
of skull defects or plates that modify the intensity and distribution of electrical currents.
The authors touch on the interesting areas for future study in TBI including:
augment learning and memory, recovery from disordered consciousness, and using NBS in
combination with other therapies, such as physical therapies. A recommendation is put
forward for further research using NBS in TBI patients, to give specific attention to the type
of stimulation (mode, parameters) according to the goal of the physiological interaction, and
thus elucidate possible time-windows for specific interventions.
Villamar and colleagues provide valuable insight for TBI clinicians and NBS
researchers on safety and efficacy considerations that may shape future studies as the field
of NBS in TBI unfolds. The heterogeneity of traumatic brain injuries and the complex
pathophysiology that varies with time since injury, make it unlikely that any specific NBS
protocol will be beneficial for all TBI patients. If individualized treatments are developed
targeting known pathophysiology, we stand the best chance of enhancing recovery and
decreasing the magnitude of disabling sequelae after the injury.
Dylan Edwards, PhD
New York, NY, USA
CITATION: Villamar, M. F., Santos Portilla, A., Fregni, F. and Zafonte, R. (2012), Noninvasive
Brain Stimulation to Modulate Neuroplasticity in Traumatic Brain Injury. Neuromodulation:
Technology at the Neural Interface, 15: 326–338. doi: 10.1111/j.1525-1403.2012.00474.x
Successful treatment of testicular pain with peripheral nerve stimulation of the
cutaneous branch of the ilioinguinal and genital branch of the genitofemoral nerves
PUBLIC COMMENTARY:
This is an interesting case report that expands on previously published (and referenced in
the paper) cases of testicular pain control with peripheral neurostimulation (PNS). The
authors’ point of uniqueness of their case is that they postulate that different electrodes
separately and specifically stimulated ilioinguinal and genitofemoral nerves – supporting
this with the course of the electrode leads and distribution of paresthesias.
However, one has to take into consideration individual variability – not only in the
anatomical course of each nerve, but also in the pattern of sensory distribution – and the
fact that due to the fascicular arrangement inside the nerve it is conceivable that stimulation
of the same nerve from different direction may produce different paresthesia patterns.
What important in this case, just like in any other – is the clinical outcome, and with
adequate pain relief it is probably not as crucial to know what exactly the stimulation target
/ substrate was. From the recommendation point of view, however, it may be reasonable to
start routinely integrating intraoperative imaging into our PNS procedures, particularly
since it is now becoming an integral part of armamentarium in the pain-treating community
and since multiple successful clinical applications of ultrasound-guided PNS have already
been reported in extremities and occipital region (1-5). As the matter of fact, one of the first
clinical applications of this technique did indeed involve localization of ilioinguinal nerve
during PNS trial (6).
As most neurosurgeons, I am not personally familiar with ultrasound application in
visualizing peripheral nerves – and don’t know whether it is even feasible to identify and
differentiate ilioinguinal and genitofemoral nerves – but maybe it is time for me and my
colleagues to learn this adjunctive modality as it may make PNS procedure faster, more
precise and safer, translating in turn into a better pain relief and improved overall success
rate.
Konstantin V. Slavin, MD
Chicago, IL, USA
References:
1. Huntoon MA, Huntoon EA, Obray JB, Lamer TJ: Feasibility of ultrasound-guided
percutaneous placement of peripheral nerve stimulation electrodes in a cadaver model:
Part one, lower extremity. Reg Anesth Pain Med 2008;33:551–557.
2. Huntoon MA, Hoelzer BC, Burgher AH, Hurdle MF, Huntoon EA: Feasibility of ultrasoundguided percutaneous placement of peripheral nerve stimulation electrodes and anchoring
during simulated movement. II. Upper extremity. Reg Anesth Pain Med 2008;33:558–565.
3. Narouze SN, Zakari A, Vydyanathan A: Ultrasound-guided placement of a permanent
percutaneous femoral nerve stimulator leads for the treatment of intractable femoral
neuropathy. Pain Physician 2009;12:E305–E308.
4. Huntoon MA, Burgher AH: Ultrasound-guided permanent implantation of peripheral
nerve stimulation (PNS) system for neuropathic pain of the extremities: original cases and
outcomes. Pain Med 2009;10:1369–1377.
5. Skaribas I, Aló K: Ultrasound imaging and occipital nerve stimulation. Neuromodulation
2010;13:126–130.
6. Carayannopoulos A, Beasley R, Sites B: Facilitation of percutaneous trial lead placement
with ultrasound guidance for peripheral nerve stimulation trial of ilioinguinal neuralgia: a
technical note. Neuromodulation 2009;12:296– 299.
CITATION: Rosendal, F., Moir, L., de Pennington, N., Green, A. L. and Aziz, T. Z. (2012), Successful
Treatment of Testicular Pain With Peripheral Nerve Stimulation of the Cutaneous Branch of the
Ilioinguinal and Genital Branch of the Genitofemoral Nerves. Neuromodulation: Technology at the Neural
Interface. doi: 10.1111/j.1525-1403.2011.00421.
Spinal Cord Stimulation versus Reoperation in Patients with Failed Back Surgery
Syndrome: An International Multicenter Randomized Controlled Trial (EVIDENCE
Study)
PUBLIC COMMENTARY:
We have long debated the relative benefits and weaknesses of percutaneously implanted
coaxial leads versus surgically implanted paddle type leads for spinal cord stimulation.
Percutaneous leads are less traumatic to implant and are easy to navigate within the
epidural space. On the other hand, they provide circumferential stimulation including that
of the intended spinal cord as well as extraneous, potentially pain inducing targets such as
the dorsal and lateral ligamentous and periosteal structures. In addition, they are less
efficient, require greater power to generate a comparable degree of stimulation and
produce different electrical fields than those produced by paddle type leads. Surgically
implanted paddle leads provide unidirectional stimulation and are much more efficient due
in part to their much larger area of electrode contact with the dura. These leads, however,
require open surgical trauma to implant and are relatively unmanuverable within the
epidural space. Vonhogen and colleagues provide their experience with a much needed
synthesis of these two approaches: a percutaneously delivered paddle lead. Their
retrospective results suggest that this is a less traumatic and possibly equally effective
technique for spinal cord stimulation when compared to traditional paddle type leads.
While I believe that this is a valuable and important study, I do believe that we should look
upon the conclusions with some caution. The implantation of a paddle lead through a large
Tuohy needle by unskilled hands raises the potential for significant dural puncture and/or
spinal cord injury. This suggests the need for a safer alternative delivery system; such
systems are currently available in Europe. One hopes that such devices will become
available soon in the United States. Furthermore, before comparative conclusions can be
made, we need head to head prospective randomized trials to determine relative efficacy
and complication rates. Particular attention should be paid to the potential complications of
implantation and the longevity of the effect to determine whether larger surgically
implanted paddle leads provide better long term efficacy when compared to the smaller
percutaneously implanted paddle leads or whether these percutaneously implanted smaller
paddle leads are safer than larger surgically implanted leads.
Nonetheless, I laud the authors on their successful experience thus far and look forward to
future studies in this area.
Robert M. Levy, M.D., Ph.D.
Jacksonville, FL, USA
CITATION: North, R. B., Kumar, K., Wallace, M. S., Henderson, J. M., Shipley, J., Hernandez, J.,
Mekel-Bobrov, N. and Jaax, K. N. (2011), Spinal Cord Stimulation Versus Re-operation in
Patients With Failed Back Surgery Syndrome: An International Multicenter Randomized
Controlled Trial (EVIDENCE Study). Neuromodulation: Technology at the Neural Interface,
14: 330–336. doi: 10.1111/j.1525-1403.2011.00371.x