In accordance with regional recommendations for the prescription of cannabinoids, medical cannabis treatment was proposed to six patients followed-up in the Centro Regionale Veneto di Cure Palliative Pediatriche e Terapia del Dolore of Padova Hospital, Italy – a referral center for PPC in northern Italy – who were suffering from treatment-resistant epilepsy and/or chronic pain and/or spasticity resistant to standard treatment lines, without contraindication to the use of medical cannabis due to psychiatric or cardiovascular disease. Data presented here cover an observation period of 1 month before initiation of cannabis, and 12 months during treatment. The previously prescribed antiepileptic and analgesic therapy were continued in concomitance with cannabis. Patients’ characteristics are reported in Table 1, treatment dosage is reported in Table 2, and the effect of treatment on symptoms is summarized in Table 3.
Table 1
Course of treatment with FM2, with clinical outcomes
| Patient | Starting/maximal dose (mg/kg/day) | Titration changes (n) | Daily frequency of seizures (beginning/best result; features) | % of days free from seizures (beginning/best result) | % of days free from pain (beginning/best result) | Adverse events with dose of FM2 at occurrence |
| 1 | 0.11/059 | 10 | 0.11/0.26; tonic–clonic | 89/89 | 100/100 | No |
| 2 | 0.11/0.52 | 9 | 8/2.31 | 0/0 | 3/82.8 | Drowsiness with 0.52 mg/kg/day |
| 3 | 0.1/0.48 | 3 | 3.57/2 | 0 / 33 | 28/100 | Euphoria with 0.1 mg/kg/day |
| 4 | 0.1/0.22 | 4 | 0.79/1 | 57/73 | NA | Drowsiness: resolution with schedule change from 0.4 ml × 3 to 0.3 + 0.4 + 0.8 ml each day |
| 5 | 0.12 | 2 | 5/3; absence and tonic–clonic | 0/NA | 25/58 | Drowsiness: remission with schedule change from 0.65 ml three-times/day to 0.5 + 0.5 + 0.9 ml/day |
| 6 | 0.71/1.2 | 6 | 0.23/0.14 | NA | NA | Irritability with 1.2 mg/kg/day: dose reduction to 0.85 mg/kg/day Euphoria with 0.6 mg/kg/day: spontaneous resolution |
Table 2
Treatment dosage, according to THC content (mg/kg/day).
| Patient | Dosage changes (n) | Maximal dose (mg/kg/day) | Effective dose (mg/kg/day) |
| 1 | 7 | 0.59 | 0.55 |
| 2 | 5 | 0.52 | 0.38 |
| 3 | 4 | 0.48 | 0.48 |
| 4 | 4 | 0.62 | 0.22 |
| 5 | 4 | 0.2 | 0.2 |
| 6 | 3 | 1.2 | 0.44 |
Table 3
Symptom improvement following treatment with FM2, as evaluated by caregivers.
| Patient | Seizures | Pain | Spasticity | Restlessness | Sleep disorder | Reduced relationship |
| 1 | +/- | +/- | - | NA | - | + |
| 2 | + | + | - | + | + | - |
| 3 | + | + | + | + | + | + |
| 4 | +/- | - | + | - | + | + |
| 5 | + | + | - | + | - | + |
| 6 | + | + | - | - | + | + |
| +: Improvement of symptoms; +/- : Mild improvement of symptoms; - : No improvement of symptoms; NA: Not available. |
Medical cannabis
Patients were treated with cannabis FM2, produced by Stabilimento Farmaceutico Militare, Florence, Italy [19]. FM2 is a powder of unfertilized female inflorescences containing 5–8% THC and 7.5–12% CBD. FM2 was prepared every month as galenic 10% extract in olive oil [20], and administered alone or in lipophilic beverages, either orally or enterally, three-times/day. Titration of THC and CBD was measured by liquid chromatography column mass spectrometry and recorded every month. The therapeutic dosage was referred to the THC content of the preparation. The minimal starting dose was 0.1 mg/kg/day and was increased after at least 7 days of 0.1 mg/kg/day, up to the minimal effective dose (maximal dosage was 1 mg/kg/day). According to the efficacy criteria of regional recommendations, the dose could be increased only if pain were not reduced by ≥ 20% or the number/duration of seizures was not reduced by ≥ 30%.
Assessments
The following data were recorded: daily frequency of seizures (treatment success was defined as reduction ≥ 50% of seizures frequency) and use of rescue therapy [21–23]; pain intensity on an indirect numeric rating scale (NRS), frequency of pain flare and use of analgesics; changes in sleep, behavior, relationship, appetite and spasticity; the impact of treatment on the quality of life of the patient’s family; and adverse events. The patient’s main caregiver filled in the Italian version of the Pediatric Quality of Life Inventory TM (PEDsQL) questionnaire [24] at baseline and every 3 months up to 1 year of cannabis treatment, assisted by a psychologist. The questionnaire contains 5 subscales evaluating the caregiver (health and physical activity, emotional condition, social life, cognition, and communication, cares), and two subscales evaluating the family (daily life activities and relationships within the family). Answers were given on a 5-point Likert scale (high scores indicated a low impact and low scores indicated a serious impact).
Ethics
Written consent was released by caregivers. The procedures followed and described here were in accordance with the Declaration of Helsinki as revised in 2013.
Patient #1
A 4-year-old boy, with epileptic encephalopathy and mixed chronic pain, had mild spasticity, sleep disorder, and severe neurological impairment. He was nourished by percutaneous endoscopic gastrostomy (PEG) and had a bodyweight of 13 kg. Uncontrolled epilepsy was the main complaint, and irritability episodes were frequent and were interpreted as the result of poor pain control. Data collection started 27 days before FM2 treatment, in a period without interventions on therapies and/or care. Before initiation of cannabis, the patient was free from pain on 23/27 (85%) days. In total, 15 tonic–clonic seizures occurred in 27 days (0.6/day), and 22/27 days (81.5%) were free from seizures. All seizures presented in a cluster, and 14/15 seizures led to oxygen desaturation. Seizures rescue therapy was used four-times.
FM2 treatment started with the dose of 0.11 mg/kg/day, which was increased weekly up to 0.59 mg/kg/day, without adverse events (Table 4).
Table 4
Course of treatment with FM2, with clinical outcomes
| | Dose (mg/kg/day) | Titration (mg/ml) | Duration (days) | Seizure n (daily frequency); features | Days free from seizures | Pain | Days free from pain (%) | Adverse events |
| Patient 1 |
| Starting dose | 0.11 | THC 5.2% CDB 6.2% | 9 | 1 (0.11) Tonic-clonic, no O2 desaturation | 8/9 | No | 9 (100) | No |
| Change 1 | 0.21 | continued | 15 | 9 (0.6); Tonic-clonic, with O2 desaturation in 8/9 | 12 | No | 15 (100) | No |
| Change 2 | 0.41 | continued | 9 | 3 (0.33) with O2 desaturation | 7 | no | 9 (100) | |
| Change 3 | 0.52 | THC 5.2% CBD 12.5% | 70 | 42 (0.6); O2 desaturation in 37/42 | | yes | 67 (96); analgesiscs 5-tims | no |
| Change 4 | 0.59 | THC 5.2% CDB 8% | 24 | 9 (0.38); with O2 desaturation | | yes | 21 (87.5) | |
| Change 5 | 0.55 | THC 5.1% CDB 8.3% | 69 | 36 (0.52); O2 desaturation in 34/36 | | yes | 65 (94.2) | |
| Change 6 | continued | THC 5.2% CDB 8.4% | 36 | 18 (0.5); O2 desaturation in 18/18 | | no | 36 (100) | |
| Change 7 | continued | THC 4.7% CDB 7.6% | 43 | 11 (0.26) | | yes | 37 (86) | |
| Change 8 | 0.42 | THC 4.5 %; CDB 7.4% | 37 | 12 (0.32) | | no | 37 (100) | |
| Change 9 | 0.56 | THC 4.5%; CDB 7.3% | 29 | 10 (0.34) | | no | 29 (100) | |
| Change 10 | 0.57 | THC 4.6%; CDB 7.4% | 19 | 13 (0.68) | 17 | No | 19 (100) | |
| Change 11 | 0.55 | THC 4.4%; CDB 7.1% | 22 | 10 (0.45) | 19 | no | 22 (100) | |
| Patient 2 |
| Starting dose | 0.11 | THC 6.5%; CDB 8.5% | 33 | 266 (8) | 0 | Yes, moderate | 1 (3) | |
| Change 1 | 0.2 | continued | 33 | 191 (5.79) | 0 | moderate | 1 (3) | |
| Change 2 | 0.31 | continued | 30 | 125 (4.17) | 0 | mild | 3 (10) | |
| Change 3 | 0.34 | THC 5.8%; CDB 7.2% | 26 | 157 (6.04) | 0 | moderate | 0 | |
| Change 4 | 0.23 | THC 2.7%; CDB 9.3% | 31 | 100 (3.23) | 0 | mild | 2 (6.5) | |
| Change 5 | 0.21 | THC 1.2%; CDB 1.6% | 14 | 43 (3.07) | 0 | moderate | 0 | |
| Change 6 | 0.51 | THC 5.9%; CDB 8.3% | 30 | 80 (2.66) | 0 | mild | 14 (48.3) | |
| Change 7 | 0.52 | THC 6.1%; CDB 8.2% | 38 | 116 (3.05) | 0 | mild | 20 (52.6) | Drowsiness |
| Change 8 | 0.34 | THC 4%; CDB 6.2% | 31 | 83 (2.68) | 0 | mild | 16 (51.6) | |
| Change 9 | 0.39 | THC 4.6%; CDB 6.5% | 29 | 73 (2.52) | 0 | mild | 18 (62) | |
| Change 10 | 0.4 | THC 4.9%; CDB 6.6% | 27 | 68 (2.52) | 0 | Very mild | 18 (66.7) | |
| Change 11 | 0.38 | THC 4.6%; CDB 6.3% | 35 | 81 (2.31) | | Very mild | 20 (82.8) | |
| Patient 3 |
| Starting dose | 0.1 | na | 50 | 150 (3.57); 50 with O2 desaturation | 0 | NRS = 1 | 14 (28) | euphoria |
| Change 1 | 0.2 | | 30 | 90 (3); tonic clonic, 20 with O2 desaturation | 0 | NRS = 1 | 20 (67) | euphoria |
| Change 2 | 0.31 | THC 4.1%; CBD 2.9% | 42 | 84 (2); with O2 desaturation | 12 (29) | no | 42 (100) | |
| Change 3 | 0.28 | THC 3.7%; CBD 3.1% | 60 | 120 (2); 22 with O2 desaturation | 20 (33) | no | 60 (100) | |
| Change 4 | 0.48 | THC 5.4%; CBD 3.5% | 90 | 374 (2) | 60 (32.1) | no | 90 (100) | |
| Patient 4 |
| Starting dose | 0.1 | THC 5%; CBD 6.7% | 14 | 11 (0.79); no O2 desaturation | 8 (57) | NRS = 4 | NA | |
| Change 1 | 0.17 | continued | 9 | 15 (1.67) | 4 (44) | NA | NA | |
| Change 2 | 0.22 | continued | 53 | 60 (1.13 | 33 (62) | NA | NA | Drowsiness. Resolution with schedule change from 0.4 ml × 3 to 0.3 + 0.4 + 0.8 ml each day |
| Change 3 | Continued (0.3 + 0.4 + 0.8 ml/day) | THC 4.7%; CBD 9.9% | 60 | 79 (1.23) | 38 (59.4) | NA | NA | |
| Change 4 | 0.1 (0.4 ml × 3 daily) | THC 2%; CBD 8.9% | 84 | 85 (1) | 49 (58.3) | NA | NA | |
| Change 5 | 0.14 (0.4 + 0.5 + 0.9 ml/day) | THC 2.3%; CBD 2.9% | 27 | 34 (1.26) | 14 (52) | NA | NA | |
| Change 6 | 0.22 | THC 4.7%; CBD 5.5% | 30 | 30 (1) | 22 (73) | NA | NA | |
| Change 7 | 0.17 | continued | 30 | 30 (1) | 17 (58) | NA | NA | |
| Change 8 | 0.22 | continued | 60 | 81 (1.37) | NA | NA | NA | |
| Patient 5 |
| Starting dose | 0.12 | THC 6%; CBD 8% | 8 | 40 (5) | 0 | 3 | 2 (25) | |
| Change 1 | 0.23 | continued | 7 | 28 (4); absence and tonic-clonic | | 2 | 2 (29) | |
| Change 2 | 0.4 | continued | 15 | 60 (4) | | 2 | 7 (47) | |
| Change 3 | 0.62 | THC 6.4%; CBD 8.9% | 26 | 78 (3) | 0 | 2 | 15 (58) | Drowsiness: remission with schedule change from 0.65 ml three-times/day to 0.5 + 0.5 + 0.9 ml/day |
| Change 4 | 0.42 | continued | 77 | 231 (3) | | 2 | 44 (57) | euphoria |
| Change 5 | 0.38 | THC 5.9%; CBD 10% | 240 | 720 (3) | | 2 | | Euphoria: remission with dose reduction to 0.2, schedule 0.2 + 0.3 + 0.9 ml/day |
| Patient 6 |
| Starting dose | 0.71 | THC 6.74% | 39 | 9 (0.23) | | Analgesics 12-times | | |
| Change 1 | 1.2 | THC 11.5%; CBD 14.1% | 27 | 6 (0.22) | NA | Analgesics 9-times | | Irritability: dose reduction to 0.85 mg/kg/day |
| Change 2 | 0.4 | THC 5.42%; CBD 7.87% | 86 | 13 (0.15) | | Analgesics 13-times | NA | |
| Change 3 | 0.6 | THC 10.5%; CBD 9.1% | 56 | 8 (0.14) | NA | Analgesics 13-times | NA | Euphoria: spontaneous resolution |
| Change 4 | 0.4 | THC 4.8%; CBD 7.4% | 38 | 6 (0.16) | NA | Analgesics 10-times | NA | |
| Change 5 | 0.44 | THC 4.14%; CBD 5.61% | 84 | 28 (0.33) | NA | Analgesics 64-times | 20 (23) | Reduced appetite |
| Change 6 | 0.49 | THC 4.6%; CBD 6.16% | 28 | NA | NA | No pain | 0 (100) | Restlessness and tachycardia |
Overall, fairly good control of pain was obtained, with a 15% increase of days free from pain. The proportion of days without seizures was 81.5% before the use of cannabis and was slightly reduced during the first month of treatment; it was then progressively increased, up to 90%. The intensity of seizure clusters was reported by the caregiver to be reduced. An overall reduction of irritability and an improvement of relationships were observed.
The PedsQL questionnaire showed that the disease impact on the family was reduced after 1 year of cannabis use (total score was 47.92 at baseline and 59.72 at observation end). Improvement was obtained in the subscales emotional condition, care, daily life activities and family relationships.
Patient #2
An 18-year-old boy, affected with lissencephaly, severe neurological impairment, nourished by PEG, with a bodyweight of 33 kg, and spasticity, had drug-resistant epilepsy on treatment with benzodiazepines, phenobarbital, valproate and topiramate. He also received gastroprotective drugs and food supplementation. He suffered from chronic mixed pain, resistant to treatment with NSAIDs + opioids + corticosteroids. He was observed for 13 days before starting cannabis treatment while continuing the previously prescribed therapy. The pain was reported each day, in this period, with a mean NRS scale intensity = 3.5. Overall, 113 seizures occurred, with a daily frequency = 8.7, and no days were free from episodes. Seizures presented as spasms in 41 cases and tonic–clonic episodes in 72 cases. Seizures never led to oxygen desaturation, and rescue therapy was not used.
FM2 dose was initially 0.11 mg/kg/day and increased weekly up to 0.52 mg/kg/day (Table 4). The patient tolerated the treatment with FM2, with only a transient episode of drowsiness. He obtained an improved control of pain (from 0 days without pain to 80% of days without pain), which was moderate before treatment, together with a relevant reduction of seizure frequency, from 8.7/day to 2.3/day. At the end of the observation, the impact of disease on the family quality of life was not changed, as the PedsQL total score was 34 at baseline and 37 at 12 months after initiation of cannabis. A little improvement was observed in the subscales emotional condition, social life and cognition, while the impact on care and daily life activities was increased.
Patient #3
A 19-year-old boy who had a kidney transplant was affected with coenzyme Q10 deficiency, nurtured by PEG, and had a bodyweight of 34 kg. Chronic mixed pain, severe neurological impairment, mild spasticity and agitation were present. He was treated with benzodiazepines, phenobarbital, oxcarbazepine, proton pump inhibitors, corticosteroids and immunosuppressors. On-demand analgesic treatment was based on NSAIDs + opioids + corticosteroids. During the pre-cannabis 30-day period of observation, he received analgesics 12-fold, and the mean pain intensity, as caregiver-evaluated NRS was 4; 12/30 (40%) days were free from pain. Seizures occurred every day with a frequency of 6 episodes/day (total number of seizures was 180); all seizures were tonic–clonic, and 120 episodes lasted > 5 minutes; rescue therapy was administered three-times.
FM2 was started with 0.1 mg/kg/day and the dose increased weekly up to 0.48 mg/kg/day. At the highest dose, the patient had mild euphoria, which spontaneously remitted (Table 4).
He obtained a relevant reduction of seizure frequency (2 seizures/day) and pain control (zero analgesic treatment) with the use of medical cannabis; in addition, a positive effect was observed on spasticity, agitation, sleep disorder and relationship.
The disease impact on the family quality of life was reduced after 1 year of treatment with medical cannabis. The total PEDsQL score was 18 at baseline and 38 at the observation end. Improvements were observed in the areas of health and physical activity, emotional condition, social life, cognition, communication, care and family relationships. Only the impact on daily life activities was unchanged.
Patient #4
A 14-year-old girl was affected with Rett’s syndrome, had moderate cognitive dysfunction, and had no particular pain. She had a bodyweight of 35 kg, was nurtured by PEG, presented with mild spasticity and restlessness. Antiepileptic treatment was based on valproate and benzodiazepine when needed; she also received a proton pump inhibitor and food supplementation. During the 30 days of observation before cannabis initiation, she had 58 tonic–clonic seizures (1.9/day), 33 of which lasted > 5 minutes; 9 (30%) days were free from seizures. No pain was reported from caregivers, but daily episodes of restlessness were observed. FM2 treatment was initiated with the daily dosage of 0.1 mg/kg/day, and the dose increased up to 0.22 mg/kg/day (Table 4).
Drowsiness was observed with the maximal dose; this adverse event resolved after the dosage schedule was changed from 33% of total dose three-times/day to 20%+30%+50% of total dose respectively in the morning, afternoon and evening. Overall, the patient obtained a limited reduction of seizure frequency and restlessness, while spasticity, sleep and relationship ability were improved.
The disease impact on the family quality of life was little changed after 1 year of treatment; PedsQL total score was 52 at baseline and 54.8 at observation end. While the score in the social life subscale was improved from 75 to 175, the emotional condition score deteriorated from 250 to 175.
Patient #5
A 17-year-old boy, with a bodyweight of only 20 kg, affected with epileptic encephalopathy, severe psychomotor impairment, had mixed pain, spasticity, restlessness and sleep disorder. He was treated with benzodiazepines, valproate, topiramate and baclofen, with proton pump inhibitor and food supplementation. Analgesic therapy was based on NSAIDs, opioids and corticosteroids. He was observed for 30 days before initiation of cannabis. In this period, mean pain intensity at NRS scale was 7, analgesic treatment was used 16-times, and 8/30 (27%) days were free from pain. He had 300 (10/day) absence and tonic–clonic type seizures, all lasting < 5 minutes and without oxygen desaturation. No days free from seizures were observed.
FM2 treatment was started with 0.12 mg/kg/day, and increased weekly to 0.62 mg/kg/day. At the maximal dose, drowsiness occurred and remitted after the administration schedule was changed from 33% of total dose three-times/day to 25% + 25% + 50% of total dose in the morning, afternoon and evening, respectively. After dose reduction to 0.42 mg/kg/day, euphoria occurred and remitted after the dose was reduced to 0.2 mg/kg/day, of which 15% + 20% + 65 % was administered in the morning, afternoon and evening, respectively (Table 4).
Overall, in addition to a relevant improvement of pain (mean NRS changed from 7 to 3, and 57% of days free from pain) and seizures (3 seizures/day), this patient obtained a reduction of restlessness and improvement of relationship ability.
The total PedsQL score was 41 at baseline and was increased up to 56 at the observation end. The areas that improved after 1 year of treatment with cannabis were health and physical activity, emotional condition, care, daily life activities and family relationships. On the contrary the impact on social life, cognition and communication was not improved.
Patient #6
A 5-year-old female child, affected with epileptic encephalopathy, severe psychomotor impairment, moderate pain associated spasticity, with NRS as high as 10 (caregiver report). She also had restlessness and sleep disorder. Therapy was based on benzodiazepines, phenobarbital and oxcarbazepine. She received a proton pump inhibitor and food supplementation. The pain was treated with NSAIDs, opioids and baclofen.
Before FM2 treatment, she had 300 (10/day) absence and tonic–clonic type seizures, without oxygen desaturation. Pain occurrence and intensity were not recorded.
At the beginning of the observation period, she was being treated with FM20.71 mg/kg/day, prescribed by another center. Involuntarily, the dosage was increased to 1.2 mg/kg/day due to high titration (11.5% THC, 14.1% CBD), for 1 month (Table 4). As irritability ensued, the dosage was progressively reduced to 0.44 mg/kg/day.
During treatment with FM2, she had some adverse events: irritability requiring dose reduction, euphoria, loss of appetite, restlessness and tachycardia which remitted spontaneously.
Through the observation period, this patient obtained an improvement of sleep disorder and relationship ability; the caregiver reported a reduction of pain intensity (reduced use of analgesics) and seizure frequency (0.33/day). The impact of disease on family quality of life could not be evaluated.