FormalPara Key Summary Points

Why carry out this study?

While there is literature support for the value and application of certain intravenous barbiturates in the diagnosis of chronic pain conditions, only sodium pentobarbital (SP) is clinically available for such use and under very restricted conditions.

The objective of the study was to document the value of intravenous SP as a diagnostic tool in elucidating the origin of pain generators in patients with chronic pain.

What was learned from the study?

This is the first pragmatic practice-based study that supports the value of intravenous SP as a diagnostic tool in elucidating chronic pain.

Introduction

Bleckwenn [1] in 1930 was the first physician to use intravenous sodium amytal or amobarbital (IV SA for the purposes of this report), a short- to intermediate-acting barbiturate, to treat certain patients with psychosis by inducing “narcosis” via “barbiturate-assisted interview.”

The application of IV SA (or SA interview), specifically as a diagnostic aid for chronic non-cancer pain, has been studied extensively and reported by our group at the Toronto Western Hospital/University Health Network (a large hospital conglomerate in downtown Toronto, Ontario, Canada), with numerous studies conducted between 1988 and 2017 [2,3,4,5,6,7,8,9,10,11]. SA was discontinued in Canada in 2003, and the pain team had to resort to sodium pentobarbital (SP), an isomer of amobarbital known as Nembutal [12].

The aim of the present paper is as follows:

  1. 1.

    To present a comprehensive narrative literature review [13] of barbiturates regarding their evolution and applications, particularly those related to SA and SP interviews, as well as current accessibility challenges to obtaining these drugs for diagnostic purposes

  2. 2.

    To report the results of a research study performed with IV SP in a series of consecutive patients admitted for pain investigations at the Toronto Western Hospital (2004–2009), describing in detail the effect of SP interviews on pain and sensory abnormalities

  3. 3.

    To demonstrate the utility of SP interview in the diagnosis and management of patients with chronic pain by citing illustrative case reports [14]

To reach the broadest possible external audience interested in barbiturate use for chronic pain assessment as a diagnostic tool, a mixed-methods study approach was used. Notably, the narrative review serves as a background in the introduction and focuses on information on the use of barbiturates in chronic pain from a historical perspective and current challenges. Our comprehensive review met the SANRA (Scale for Assessment of Narrative Review Articles) guideline criteria for narrative literature review [15] and was conducted as follows: We searched the literature for English-language studies on SA, SP, and pain management in a comprehensive search for the period from 1922 onward. We used the following combinations of keywords in pain medicine and clinical practice: barbiturates, chronic pain, sodium amytal, sodium pentobarbital, and sodium pentobarbital practice. We attempted to include as many recent manuscripts as possible, as well as older papers if they were relevant to our topic. We further attempted to search for “use” and cite the primary manuscripts whenever possible.

Part 1: Background

Historical Perspective/Literature Review

Barbiturates were first manufactured by J. von Liebig in 1832 and later modified by O. Liebreich [16]. However, their application in clinical practice started around 1904, when the Farbwerke Fr Bayer and Co. brought to the market diethylbarbituric acid. This was followed by profound changes in the pharmacological treatment of psychiatric and neurological disorders of the time [16].

Indeed, barbiturates became the first pharmacological agents that showed efficacy in treating many previously untreatable psychiatric patients and in improving their (otherwise dismal) prognosis, specifically those with severe neuroses, psychoses, and associated emotional repression. Intravenous administration of barbiturates assisted psychotherapeutic treatments by overcoming patients’ “emotional inhibitions.” Furthermore, barbiturates have become useful treatments for sleep disorders, epileptic seizures, and anesthesia induction in minor surgeries [17]. It is telling that during the twentieth century, approximately 2500 barbiturates were synthesized, with 50 of those having clinical applications [17]. Two barbiturates have gained notoriety for their specific use in certain patients with psychosis, namely amobarbital or sodium amytal (a short- to intermediate-acting barbiturate), synthesized by Shonle and Moment (Eli Lilly Company, Indianapolis, USA) in 1923, and pentobarbital (Nembutal®), a shorter-acting barbiturate synthesized by Volwiler and Tabern (Abbott Laboratories) in 1930 [17].

Bleckwenn defined induction of “narcosis” as a “state of deep sleep or unconsciousness, more or less prolonged, and quite rapidly induced by means of drugs; a condition similar to the state of general anesthesia necessary for surgical operation, but not as profound” [18]. He was indeed the first physician to use sodium amytal or amobarbital (SA) interview in 1930 to treat certain patients with psychosis, inducing a catatonic state temporarily in patients with schizophrenia and allowing brief “cures,” which were quite customary in European asylums in the 1930s and 1940s [19]. During and after World War II, IV “narcoanalysis” became a specialized technique combining narcosis with psychotherapy [1].

In addition to its use in narcoanalysis, SA interviews have been used extensively in the intracarotid amytal test (IAT) or Wada test as a diagnostic tool for evaluating refractory epilepsy [19] and in veterinary euthanasia [20], as SA is approved by the US Food and Drug Administration (FDA) as a schedule II drug for multiple uses. The beneficial effects of IV SA administration have been further reported in several psychiatric functional disorders besides psychosis (e.g., psychogenic amnesia or fugue states, post-traumatic stress disorder [PTSD], conversion disorder) [1, 18].

The SA interview in forensics as a deception detection test (DDT) (hence the name “truth serum”) has been popularized in movies, although there have been considerable objections regarding its value in eliciting truth from involuntary subjects. In a landmark judgment, the Apex Court of India in 2004 stated that the test cannot be used without consent [21]. At present, SA for this purpose has fallen into disrepute.

In regard to SA interview for use in diagnosing chronic pain, several studies and reviews of its application as an investigational/diagnostic tool in patients with chronic pain have been published by our group at the Toronto Western Hospital/University Health Network. Many of our studies have been performed using single-blinded infusions of SA and normal saline (NS) [2,3,4,5,6,7,8,9,10,11], and have shown that IV SA seems to exert numerous effects in patients with different types of pain.

Current Situation: Accessibility Challenges

When SA was discontinued in Canada in 2003, the pain team resorted to SP as a replacement. Sodium pentobarbital is an isomer of amobarbital known as Nembutal. SA and SP are similar in action, except that pentobarbital works slightly faster, is shorter-lasting, and is easier to tolerate [22]. A literature review revealed a dearth of research on SP and its effect on pain. Pentobarbital was reported to prevent the development of C-fiber-induced hyperalgesia in experimental animals [23]. In humans, there is extremely limited literature regarding the use of IV SP to help distinguish “organic” (biomedical) disorders from psychiatric disorders such as conversion disorder, somatization, and somatoform disorders [24]. In a single case report, SP interview facilitated examination of an active-duty US soldier who presented with right-hand treatment-resistant complex regional pain syndrome and PTSD. During the SP interview, the patient was observed to spontaneously use his right hand with no evidence of pain or movement restriction. The SP interview with follow-up hypnotherapy resulted in total resolution of his pain, return to duty, and full functionality, and prevented further extensive, potentially dangerous, and ineffective therapies [25].

SP was obtained by our team in 2003 via a special application to Health Canada for strict investigational purposes in inpatients with chronic pain. However, over the past few years, our pain team has faced increasing difficulties in acquiring the drug from Health Canada for inpatient pain investigations.

Data on SP administration were collected systematically up to 2009 from a large series of consecutive inpatients. Research ethics board approval was obtained for retrospective chart review, and preliminary analysis was presented in poster format. However, significant administrative and funding changes in our institution resulted in staff changes and reorganization/transfer of the original inpatient program to a different hospital site. Additionally, the COVID pandemic led to the closure of our inpatient program for more than 2 years and additional difficulties in obtaining SP from Health Canada as we reopened the hospitals. All of these factors resulted in lack of further systematic collection of data.

Given the paucity of published studies on IV SP and the increasing difficulties faced in obtaining SP for investigations of inpatients with chronic pain (with the risk that the inpatient program will have to cease permanently because of the lack of SP), we felt that it was important to complete the data analysis, provide a literature review, and submit our study for publication.

Part 2: Original Research Study

Methods

The study is a descriptive practice-based pragmatic study of 176 consecutive patients with chronic non-cancer pain longer than 6 months who were admitted for multidisciplinary team assessment to elucidate the underlying pathology in the inpatient unit of the Comprehensive Pain Program (CPP), a university-affiliated tertiary care pain clinic in Toronto, Ontario, over a period of 6.5 years (2004–2009). This study was reviewed and approved for retrospective chart review by the institutional research ethics board (UHN REB number: 09-0302-AE) and was conducted in accordance with the Declaration of Helsinki. All admitted patients signed informed written consent forms (outlining the anonymous use of their data in an aggregate format for research purposes as well as consent for administration of IV drugs.

Procedural Protocol

Single-blinded NS-controlled barbiturate infusion has been an established practice at the CPP since 1994 as part of a comprehensive battery of tests for multidisciplinary investigations of chronic pain inpatients and is considered a standard and routine clinical investigative tool. It has been applied to all inpatients (all of whom were suspected of having psychological factors contributing to enhanced pain perception irrespective of the presence of biomedical pain generators). In this study, all inpatients were naïve to treatment (i.e., had never tried IV barbiturates before) and were administered a single-blinded NS-controlled infusion of SP. NS was infused first (5–10 ml, 1 ml/min) over a period of 10 min, followed by SP (3–5 mg/kg, 40 mg/ml/min, maximum 400 mg, except in cases where the patient showed no signs of sedation whatsoever, at which time the dose was increased to 600 mg in total). We used a maximum of 400 mg for the SP study, as opposed to 500 mg in our SA studies, due to the slightly faster action of SP. For this procedure, the patients (in limited cases there were other than barbiturate infusions) signed an informed consent form stating the following: “I understand that I will receive IV administration of any one or two of the following: lidocaine, normal saline, phentolamine, or sodium pentobarbital. I understand that I will not be told which drug(s) I will receive or in which order until the date of discharge. I also understand that I may feel no effect at all or that I may become lightheaded, dizzy, develop a stuffed nose, feel relaxed, happy, or sad, and that my pain may increase, decrease, or not change at all.” Therefore, the patients (but not the primary investigator) were blinded to the drugs they received during the NS/SP procedure. Since the instructions are neutral (i.e., providing general but not specific information for each drug and indicating both positive and negative effects as possible outcomes), patients did not know exactly what to expect. Videotaping was performed for each infusion after further signed consent was obtained. The protocol for IV SP used since 2003 is similar to that for SA, another intermediate-acting barbiturate available prior to 2003 in Canada, after which the drug became unavailable (protocol described by Mailis et al. 1997) [4, 5]. Of note, only single-blinded infusions were possible, as our inpatient beds were housed in an acute care hospital, and therefore patient stay was quite short.

For the study patients, we used the term IV SP instead of SP interview given the addition of a single-blinded infusion of NS.

High opioid doses or excessive alcohol consumption might result in “tolerance” and “resistance” to the drug's effects. However, only a few patients in the study group were using low-dose opioids; therefore, their treatment had no impact on the investigation.

Data Collection

The demographic information of the study participants was collected at the time of referral to the CPP, and the final team diagnosis (upon discharge) was retrieved from chart review. Pain ratings (0–10 numeric rating scale, NRS) and sensory abnormalities to light touch and pinprick (via a soft brush and pinwheel) were drawn in body diagrams (by the patient at baseline) and documented after each infusion (by the physician administering the infusion). The outcome evaluator was blinded throughout the study to prevent bias and ensure objective, reliable, and accurate results.

Diagnostic Classification

The diagnostic classification in terms of pain mechanisms was derived from extensive history-taking, detailed physical examination, and review of imaging, electrophysiological investigations, surgical reports, and other records. Regarding the underlying pain mechanisms, patients were categorized as having neuropathic pain condition(s) (NP), nociceptive pain condition(s) (NC), or a combination of both (NP/NC). Examples of neuropathic conditions include diabetic neuropathy, traumatic neuropathy, complex regional pain syndrome, and chronic spinal radiculopathy. Examples of nociceptive conditions include osteoarthritis, scoliosis, and plantar fasciitis. However, a fourth subgroup with no evidence of peripheral pathology but significant pain and related disability was coded as group X. The term “nociplastic” is a term recently adopted by the International Association for the Study of Pain (IASP) [26], serving as an umbrella mechanism for pain conditions such as widespread pain or regional pain that lack evidence of discrete peripheral damage and are associated (only) with increased sensitivity to multiple stimuli, including touch, pressure, cold, movement, and sound [26, 27]. Therefore, patients with sensory loss and lack of biomedical nociceptive or neuropathic pain generators cannot be classified as nociplastic, hence our use of the term “group X” to include patients who lack structural detectable pathology and present with either sensory gains or deficits.

Statistical Analysis

All data were analyzed using SPSS (Statistical Package for the Social Sciences v.16.0, SPSS Inc., Chicago, IL, USA). Descriptive statistics were used for the demographics, pain, and groups. Descriptive analyses consisted of means and proportions according to the nature of the variables. Inferential statistical analyses were conducted whenever possible to assess whether the relationships were statistically significant using the appropriate statistics (e.g., t, F). This was a retrospective study with no specific hypothesis testing. As such, these statistics provide only some indication, with at least a p < 0.05 level of statistical significance, of results that may not be due simply to the chance distribution of the data.

Results

The study group consisted of 83 men and 93 women (male–female ratio 1:1.1), with an average age of 41 ± 11 years. The mean pain duration for the whole cohort was 5.8 ± 6.5 years (range 1–40 years; median 3.4 years). In terms of underlying biomedical pathology, the following four subgroups were identified: 45% had neuropathic pain (NP), 12.5% had nociceptive pain (NC), and 7% had mixed neuropathic and nociceptive pain (NP/NC), whereas 35.8% lacked definable and detectable pathology after all investigations and imaging (“X group”). No differences were found among these subgroups in terms of the female-to-male ratio, age, or duration of pain symptoms (Table 1). Based on 176 pain drawings done by patients, the three most frequently reported painful body parts were lower extremity (33%), low back plus lower extremity (18%), and upper extremity (18%).

Table 1 Characteristics of the study population
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The NRS baseline pain rating prior to the initiation of infusions in the study group was 6.0 ± 2 (range 1–10). Only 13% of patients rated their pain as mild (NRS mild 1–3.9; moderate 4–6.9; severe ≥ 7), and the majority (87%) had moderate or severe pain (p < 0.0001) (Fig. 1).

Fig. 1
figure 1

Pain severity based on group classification. Over half of the patients in all group classifications fell into the moderate to severe pain category (NRS mild 1–3.9; moderate 4–6.9; severe ≥ 7). NP neuropathic pain, Noc nociceptive pain

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Pain Responses to Infusions

Pain Responses and Failure Rates

The mean NS dose was 7.8 ± 2.3 (range 2–10 ml) and mean SP dose was 223.8 ± 88 mg (range 40–420, median 200). A few patients received less than 10 ml NS due to early response and complete pain disappearance or because they developed side effects (nocebo response). One patient only received 560 mg of SP at 400 mg and showed no effects of the drug, including no signs of altered level of consciousness. This patient was not included in the calculation of mean dose.

Twenty-six out of 176 patients (15%) failed to experience any pain relief with any infusion (15% of patients with biomedical pathology and 14% of the X group). Of the remaining 150 patients (categorized as responders), 9% responded exclusively to NS infusion, 21% derived benefit first from NS and further benefit from SP (dual responders), and the remaining 70% derived benefit only from SP. There were no differences in age, pain duration, NRS score at baseline, or sex between responders and non-responders to any infusion. Of note, the X group had a much greater response to NS than the biomedical group (17% vs. 5%, respectively), but the results did not reach statistical significance, most likely due to small numbers. Table 2 displays the results.

Table 2 Pain responses per type of infusion and diagnostic group
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Magnitude of Pain Response

The mean NRS scores were reduced by 41% from baseline in those who responded exclusively to NS, 76% in those who experienced a dual response (from both NS and subsequent SP infusion), and 55% in those who responded exclusively to SP. Between the responders to either one or both SP infusions (NS/SP or SP only), the pain reduction was substantial and reached both clinical (> 2 NRS basis-point reduction) and statistical significance (p < 0.001). The results are summarized in Table 3.

Table 3 Response based on the type of infusion
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Pain Responses to NS Alone or NS/SP

The data were analyzed separately with regard to pain responses in patients with detectable biomedical pathology (biomedical group collectively consisting of patients with NC, NP, or NC/NP) and X-group patients. The biomedical group had a very small and statistically nonsignificant drop in pain with NS alone, followed by a substantial decrease in pain with NS/SP or SP alone, whereas the X group responded substantially to both NS and SP. The results are presented in Table 4.

Table 4 Pain responses of biomedical versus X group
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Characteristics of Patients Who Experienced Total Pain Relief

Complete pain relief (NRS = 0) was obtained in 57/150 responders (38%), whereas the remaining 62% (93/150) had partial relief. Of the 57 complete-pain-relief patients, pain was eliminated after NS only in seven (notably 6/7 belonged to the X group, p < 0.05), 17 had dual response (to NS first and SP afterwards), and 33 responded exclusively to SP. In regard to the underlying diagnosis, complete pain relief was obtained in 36.5% (35/96) of the biomedical group responders and in 40.7% (22/54) of the X-group patients. None of the differences proved to be statistically significant except in one subgroup as stated above.

Response of Sensory Abnormalities to Infusions

Baseline Sensory Abnormalities

Altered sensation was found in 73% of the patients at baseline (128/176). The area of altered sensation was concordant in size with the pain area in 34% of these patients, larger than the pain area in 35% of the patients, and smaller than the pain area in 27% of the patients. Only 4% of patients had altered sensation in a region remote from their pain. Based on pain drawings, the three most frequent areas of altered sensation involved the lower extremity (39%), hemibody plus face (24%), and upper extremity (18%).

Seventy-two of the 128 patients with altered sensation (56%) had a sensory deficit (reduced sensation to touch and/or pinprick) (p = 0.001); 35% (45/128) had exclusively sensory gain (allodynia and pinprick hyperalgesia), whereas a minority (9%) had mixed gain and deficit.

Response of Sensory Abnormalities and Failure Rates

Of the 128 patients with abnormal sensory findings, 60% (76/128) experienced improvement after infusion (i.e., reduction in size/intensity or elimination of the area of altered sensation) as follows: 9% (7/76) responded only to NS, split evenly between patients with definable biomedical pathology and patients in the X group, and 91% (69/76) improved after NS/SP or SP alone (with one in four displaying a dual response first to NS and then SP).

The responses differed between patients with sensory gains and those with sensory deficits, as well as between sensory abnormalities of either polarity (e.g., gains or deficits) if they were within a peripheral nerve or root territory (dermatomal) as opposed to those that were diffuse (non-dermatomal), as follows: (a) Patients with dermatomal sensory deficits due to clinically and/or electrophysiologically documented nerve or root damage had the lowest response rate to infusions (24% or 5/21). (b) Patients with non-dermatomal sensory deficits (and lack of neurological damage) had the highest response rate (58%, 28/48). However, the difference between the subgroups was not statistically significant, perhaps because of the small sample size of the first subgroup. (c) The improvement rates for sensory gains were quite high in both the dermatomal and non-dermatomal gain subgroups (83% and 74%, respectively); however, there was no statistically significant difference between the two groups. Specifically, allodynia was completely eliminated in 79% (11/14) of the cases with touch hypersensitivity relative to 47% (8/17) of those with pinprick hyperalgesia. The difference was not statistically significant, perhaps because of the small sample size. The responses of sensory gain versus deficit to infusions are summarized in Table 5.

Table 5 Sensory abnormality responses to the infusion
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Sensory gain failed to respond to either infusion in 44% (41/93) of patients with identifiable structural pathology and 31% (11/35) of the X group (p < 0.5). Altogether, the response for sensory gains (78%, 35/45) (including a minority of responders to NS exclusively) was significantly greater than that for sensory deficits (46%, 33/72, p < 0.0001), while response for pain was much higher than the response for sensory abnormalities, irrespective of sensory deficit or gain (85% for pain and 59% for sensory abnormality, p < 0.001). The results are summarized in Table 6.

Table 6 Pain versus sensory abnormality responses
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Discussion

Our SP study demonstrates results identical to those of the older IV SA interview (supporting previously reported effects of SA in patients with chronic pain) [2,3,4,5,6,7,8,9,10,11,12,13]:

  1. (a)

    Extremely high response rate to IV SP irrespective of underlying pathology

  2. (b)

    Greater response for pain than for sensory abnormality (gains or deficits)

  3. (c)

    Greater response for sensory gain than for sensory deficit

  4. (d)

    Greater response for allodynia than for pinprick hyperalgesia

Our interpretation of IV SP responses based on the results of this study is identical to that of SA documented previously in several of our papers [2,3,4,5,6,7,8,9,10,11,12,13], and we will collectively refer to our interpretation of the effects of “IV barbiturates” (implying both SA and SP) as follows:

  1. 1.

    Behaviors and signs such as tenderness, limited range of movement, disturbed gait, etc., resulting from pure nociceptive pain (i.e., fractures, inflammation, muscle tears, etc.) are only slightly altered by barbiturate infusions [6].

  2. 2.

    However, IV barbiturates may modulate the “affective” component of pain or other central effects associated with nociceptive pain generators (actual tissue damage), thus slightly reducing spontaneous pain [6].

  3. 3.

    In patients with neuropathic pain with hypersensitivity (sensory gain), IV barbiturates dramatically reduce touch-evoked pain (allodynia), which is primarily mediated by central sensitization factors, and much less pinprick hyperalgesia, while they do not alter deep pain [3, 4, 6].

  4. 4.

    In patients with neuropathic pain with hypesthesia (sensory deficit) due to damaged neural tissue, IV barbiturates may reduce spontaneous pain to a certain degree but do not change the borders of these structural anatomical deficits [3, 4, 6].

  5. 5.

    Unexplainable nonanatomical hypesthesias, most often attributable to “non-organic pain” or “conversion” phenomena, may respond dramatically to IV barbiturate administration, with a certain percentage of patients experiencing a significant reduction or total abolition of sensory deficits as well as pain [5, 6].

  6. 6.

    Abolition or significant reduction in non-dermatomal sensory abnormality and/or pain indicates a substantial central contribution, with non-fixed sensory abnormalities [6].

  7. 7.

    Persistence of non-dermatomal sensory abnormality and/or pain can be seen in (a) fixed centrally-mediated deficits or gains (with poor response to treatments), (b) malingering (conscious simulation of disease process) corroborated by other information (e.g., surveillance tapes), or (c) subconscious resistance (in patients who cling to the disabled role and resist any effort to “let go”) [6].

  8. 8.

    Early onset of confusion or disorientation with small doses of IV barbiturates may indicate organic brain syndrome [22].

  9. 9.

    Abolition or reduction of non-dermatomal sensory gain or deficit (central contributions) may enable detection of underlying structural musculoskeletal (MSK) or neuropathic (peripheral) pain generators [3,4,5].

  10. 10.

    IV barbiturates may result in full mobilization of a limb held in abnormal posture, confirming the functional nature of the condition, or to the contrary demonstrate fixed contractures [13].

Study Limitations

There was a selection bias in our sample (as most patients are known to have psychological factors, suspected to contribute significantly to the disability).

However, all infusions were single-blinded (due to the constraints of regular care within an acute care hospital), the patients were naïve to treatment (had never tried the medication before), the instructions were neutral (to avoid possible placebo or nocebo effect initiated by the examiner), the procedure was the same for both the NS and SP, and the administrator (AMG) was always the same.

Part 3: Illustrative Case Reports

Case Report #1

A 37-year-old woman was involved in a frightening car accident, after which she was seen in the emergency room (ER) with many bruises, L2–L4 transverse process fractures, and multisite pain. Within 5 months, she developed a paralyzed distal right lower extremity and multiple emotional and cognitive symptoms. Numerous investigations and treatments (electrophysiological studies, lumbar magnetic resonance imaging (MRI) scans, specialist consultations, lumbar sympathetic blocks, neuropathic medications, and analgesics) failed to provide any pain relief or document structural damage. The patient was seen 3 years after the accident and admitted to our inpatient unit for further evaluation. On examination (O/E), she was wheelchair-bound, with severe allodynia and hyperalgesia in the right leg from the groin to the ankle, but completely anesthetic (with no voluntary movement) right foot. Similar but much milder findings were observed in the left leg. Deep tendon reflexes could not be elicited in the lower limbs. She received a single-blinded NS infusion followed by IV SP as per protocol. Baseline NRS pain ratings were 5–6/10 (right leg) and 3/10 (left leg). The patient failed to respond to the NS infusion. At 80 mg of SP, she complained of dizziness, allodynia/hyperalgesia was generally reduced in both legs, right leg pain was rated 4/10 (left leg pain was much less), but distal right foot anesthesia remained. At that time, she started crying “out of joy” as she “had never felt 4/10 right leg pain since her injury.” She was instructed to close her eyes and visualize the leg. While she was able to “see” the left leg/foot, the right leg “tapered and disappeared” at the ankle. We noted spontaneous movements of the left foot while she was visualizing herself playing the piano, but this was not observed in the right anesthetic foot, while repeated commands to actively move the right foot were fruitless. At the end of the SP infusion (200 mg), the patient complained of facial numbness, double vision, and drowsiness, with sensory abnormalities significantly reduced in the left leg but unchanged in the right. Leg pain was further reduced to 3/10 or less (right leg) and 1/10 (left leg). Subsequently, the patient fell asleep.

The team (after psychological investigations, review of all consultations, and results of the SP interview) concluded that the patient had a functional neurological disorder (established shortly after her frightening car accident, which generated both physical and psycho-emotional injuries). We also considered that her sensory and motor changes were of central origin (“maladaptive neuroplasticity”), and in our opinion “permanent” in the right leg, while those in the left leg had a chance of improvement. Indeed, the patient, who was followed up for 5 years afterwards, never regained sensation or power in the right foot despite numerous treatments including neurofeedback, mirror therapy, visualization, and cognitive behavioral therapy, while she regained some power and sensation in the left foot. She continued to remain severely disabled with bilateral elbow crutches at home and wheelchair outside the house.

Take-home message: The patient’s clinical presentation with inability to “visualize” her anesthetic foot (similar to patients who have amputations) in combination with paralysis and persistence of anesthesia under SP, led the team to the conclusion that her right leg sensory abnormalities were permanent in nature. This indeed proved to be so over the many years of follow-up.

Case Report #2

A 56-year-old man developed gradual weakness, shooting pain, and loss of sensation in the left leg, which rendered him wheelchair-bound. One year later, he was diagnosed with thoracic myelopathy due to ligamentum flavum hypertrophy and underwent T9–10 laminectomy and decompression, which resulted in marked improvement in weakness and 80% pain relief. During convalescence, he developed necrotizing granuloma in the left leg that required surgery and drainage over a period of a few months. During this time, he regressed severely (both physically and emotionally) and ambulated with a wheeled walker. He was seen by our team 4 years after thoracic surgery and was admitted to our inpatient unit. Detailed psychological assessment disclosed lasting emotional trauma from loss of his government job. O/E, he had a slightly colder left foot, deep tendon reflexes were 2+ in both the upper and lower extremities, and tone, bulk, and strength were preserved. Sensory examination of the left leg, however, demonstrated a sharply demarcated and rather dense reduction of sensation to light touch, pinprick, and cold perception from the groin to the foot. His baseline back and left leg pains were 8/10. After 10 ml of NS, there was no change in sensory abnormalities or pain ratings. At 3 cc (120 mg) of SP, he experienced some drowsiness, and the sensory abnormality completely normalized, so that the sensation in the left foot to touch and pinprick was fully restored and his pain became imperceptible. The infusion was terminated at that level and the patient was left to sleep.

Given his previous thoracic surgery, the characteristics of his pain, and his response to SP, the team felt that his sensory deficit (an indication of neuroplasticity) was not permanent. After healthy life changes (diet, engagement in aqua fitness) and mindful meditation, all of which greatly improved his emotional state, we felt that the patient had become an appropriate candidate for a trial of spinal stimulation (though his sensory deficit was unchanged). Insertion of the St. Jude Medical Prodigy neurostimulation device was performed 1.5 years after SP infusion. This particular stimulator delivers closely spaced high-frequency stimulation, known as “burst” stimulation, to the spinal cord, and does not generate paresthesia in the affected limb, in contrast to classic tonic neurostimulation devices. Spinal stimulation resulted in a substantial decrease in pain and instantaneous elimination of the foot hypesthesia upon turning on the stimulator. However, when the stimulator was turned off, the sensation would immediately decrease, and the pain would increase to unbearable levels, with bursts of shooting pain from the back to the foot. To the date of this paper many years later, the stimulator effects remain unchanged.

Take-home message: Based on the SP interview, we considered that the sensory deficit was the result of central maladaptive changes which were reversible. This was indeed proven over the years of stimulator use.

Case Report #3

A 21-year-old female behavioral social worker was injured at work after one of her patients attacked her and dropped her on her left knee, resulting in knee swelling and pain. One month later, while working with crutches on modified duties, she stumbled on wet floor and fell. This was a Workers Compensation claim and the patient felt maltreated at work.

A month after her second injury, she was seen in consultation. Her pain was rated 7/10, ranging from 6/10 to 8/10. O/E, she walked with crutches while maintaining the knee in fixed 35° flexion and was barely able to move ankles or toes. The left leg was colder, with reddish discoloration in the distal foot and slight swelling in the left knee (but not foot). Sensation to light touch, pinprick, manual pressure, vibration, and cold were reduced from the left groin to the mid-shin, after which the distal leg and foot were completely anesthetic to all testing modalities.

The patient was admitted to our hospital’s rehabilitation beds with a provisional diagnosis of functional neurological symptom disorder (FND) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) and complex regional pain syndrome. She was administered a single-blinded intravenous infusion of NS followed by SP and failed to respond to 10 ml NS. However, after 200 mg of SP, the patient reported 7/10 pain, remained conscious, and the knee was passively partially extended. After 400 mg SP, her pain remained 7/10 but her sensory deficit partially normalized, and while she was awake (see Fig. 2), although somewhat sedated, we were able to fully extend the left knee passively.

Fig. 2
figure 2

Photo 1: case report 3. Near-full (left) knee extension after administration of 400 mg SP. The patient was awake, though mildly sedated

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One day later, she had returned back to her baseline. The test was repeated, but this time with a single slow infusion of 400 mg SP/1t NS over 2 h, a procedure we often performed on subsequent days with the psychologist conducting a detailed evaluation. At 200 mg, she was alert and able to extend her left knee fully, knee pain decreased to 1/10, and was able to stand up and go to the washroom unaided with straight knee full weight-bearing and landing on the left foot; however, her hip pain and sensory deficit did not improve. The next day, she rated her pain as 7/10 across the entire left leg, and while she displayed an anesthetic distal leg, her hypesthesia at the thigh and above the knee had fully resolved. Upon discharge, her knee was kept again in flexion as much as before, despite the fact she was shown photos of straight knee obtained during the SP infusion.

She refused our offer for a charge-free comprehensive pain management program (including active rehab, psychological counseling, mindfulness, nutritional counseling, etc.), while Workers Compensation had approved funding for transportation for the duration of the program.

Take-home message: Based on the SP interviews, clinical assessment, psychological assessment, and the patient’s refusal to undergo interdisciplinary pain management, the team concluded that the patient combined elements of FND (given changes in range but also sustained reduction in sensory deficit) AND conscious “simulation of disease process” as, despite her full knowledge of intact range of motion having seen photos, she denied our treatment offer and elected to pursue the role of disabled on compensation benefits.

Conclusion

The IV administration of SP to patients with chronic pain can help elucidate pain generators (central and/or peripheral) and guide prognostication and management. In particular, the effects of intravenous SP infusion were similar to those of SA infusion. Pain reduction allows appreciation of the actual range of movement, including changes in fixed posturing, while sensory abnormality changes allow appreciation of the central factors contributing to it. However, IV SP administration cannot be viewed as a tell-all diagnostic modality and must be used in conjunction with clinical judgment, investigations, and psychological reports.

Future experimental studies are needed to further explore the effects of SP (double-blind, using active comparators such as ketamine and diazepam).